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Diseases and conditions associated with tissues of the body, including but
not limited to tissues in the eye, can be effectively treated, prevented,
inhibited, onset delayed, or regression caused by administering
therapeutic agents to those tissues. Described herein are solid drug
delivery systems and methods for providing extended delivery of
therapeutic agents to such tissues. A solid drug delivery system may be
placed in a subject, including but not limited to placement between the
sclera and the conjunctiva or transscleral placement. Described methods
may be used to administer rapamycin to treat or prevent angiogenesis,
choroidal neovascularization, age-related macular degeneration, or wet
age-related macular degeneration in a subject. The solid drug delivery
devices may comprise rapamycin or other therapeutic agents. Also
described are methods of treating ocular diseases or disorders by
administering an antiproliferative agent, including but not limited to
rapamycin, proximal to an ocular device.

1. A solid drug delivery system comprising rapamycin, and wherein the
solid drug delivery system when placed between the sclera and conjunctiva
of a rabbit eye delivers an amount of rapamycin with a delivery profile
selected from the group consisting of (a) the rapamycin is delivered in
an amount sufficient to achieve, for a period of time of at least 90 days
following administration of the solid drug delivery system, an average
concentration of rapamycin in the vitreous of the rabbit eye of at least
0.01 ng/ml; and (b) the rapamycin is delivered in an amount sufficient to
achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of rapamycin in the retina choroid of the rabbit eye of at
least 1 pg/mg.

2. The solid drug delivery system of claim 1, wherein the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers an amount of rapamycin with a delivery profile
selected from the group consisting of (a) the rapamycin is delivered in
an amount sufficient to achieve, for a period of time of at least 90 days
following administration of the solid drug delivery system, an average
concentration of rapamycin in the vitreous of the rabbit eye of at least
0.1 ng/ml; and (b) the rapamycin is delivered in an amount sufficient to
achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of rapamycin in the retina choroid of the rabbit eye of at
least 10 pg/mg.

3. The solid drug delivery system of claim 1, wherein the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers an amount of rapamycin with a delivery profile
selected from the group consisting of (a) the rapamycin is delivered in
an amount sufficient to achieve, for a period of time of at least 90 days
following administration of the solid drug delivery system, an average
concentration of rapamycin in the vitreous of the rabbit eye of at least
1 ng/ml; and (b) the rapamycin is delivered in an amount sufficient to
achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of rapamycin in the retina choroid of the rabbit eye of at
least 100 pg/mg.

4. A solid drug delivery system comprising a therapeutic agent, wherein
the solid drug delivery system when placed between the sclera and
conjunctiva of a rabbit eye delivers an amount of the therapeutic agent
with a delivery profile selected from the group consisting of (a) the the
therapeutic agent is delivered in an amount sufficient to achieve, for a
period of time of at least 90 days following administration of the solid
drug delivery system, an average concentration of the therapeutic agent
in the vitreous of the rabbit eye equivalent to a rapamycin concentration
of at least 0.01 ng/ml; and (b) the the therapeutic agent is delivered in
an amount sufficient to achieve, for a period of time of at least 90 days
following administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the retina choroid of the
rabbit eye equivalent to a rapamycin concentration of at least 1 pg/mg.

5. The solid drug delivery system of claim 4, wherein the therapeutic
agent is a limus compound.

7. The solid drug delivery system of claim 6, wherein the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and
pharmaceutically acceptable salts and esters thereof.

8. The solid drug delivery system of either of claims 1 or 7, wherein the
solid drug delivery system has a backing portion that is at least
partially impermeable to the therapeutic agent.

9. The solid drug delivery system of claim 4, wherein the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers an amount of the therapeutic agent with a delivery
profile selected from the group consisting of (a) the therapeutic agent
is delivered in an amount sufficient to achieve, for a period of time of
at least 90 days following administration of the solid drug delivery
system, an average concentration of the therapeutic agent in the vitreous
of the rabbit eye equivalent to a rapamycin concentration of at least 0.1
ng/ml; and (b) the therapeutic agent is delivered in an amount sufficient
to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the retina choroid of the
rabbit eye equivalent to a rapamycin concentration of at least 10 pg/mg.

10. The solid drug delivery system of claim 9, wherein the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers an amount of the therapeutic agent with a delivery
profile selected from the group consisting of (a) the therapeutic agent
is delivered in an amount sufficient to achieve, for a period of time of
at least 90 days following administration of the solid drug delivery
system, an average concentration of the therapeutic agent in the vitreous
of the rabbit eye equivalent to a rapamycin concentration of at least 1
ng/ml; and (b) the therapeutic agent is delivered in an amount sufficient
to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the retina choroid of the
rabbit eye equivalent to a rapamycin concentration of at least 0.05
pg/mg.

11. The solid drug delivery system of claim 1, wherein the rapamycin is
present in an amount between 1% and 60% w/w of the drug delivery system.

12. The solid drug delivery system of claim 1, comprising a
polyvinylpyrrolidone in an amount between 15% and 45% w/w of the solid
drug delivery system.

13. The solid drug delivery system of claim 1, comprising a polyacrylate
in an amount between 5% and 30% w/w of the solid drug delivery system.

14. The solid drug delivery system of claim 1, wherein the rapamycin is
present in an amount between 1% and 60% w/w of the drug delivery system,
further comprising a polyvinylpyrrolidone in an amount between 15% and
45% w/w of the solid drug delivery system, and a polyacrylate in an
amount between 5% and 30% w/w of the solid drug delivery system.

15. The solid drug delivery system of claim 1, wherein the solid drug
delivery system contains between 20 .mu.g and 4 mg of rapamycin.

16. The solid drug delivery system of claim 1, wherein the solid drug
delivery system contains between 20 .mu.g and 2.5 mg of rapamycin.

17. A method for treating wet age-related macular degeneration in a human
subject, the method comprising placing the solid drug delivery system of
either of claims 1 or 4 proximal to the eye of a human subject in need of
treatment of age related macular degeneration.

18. A method for preventing wet age-related macular degeneration in a
human subject, the method comprising placing the solid drug delivery
system of either of claims 1 or 4 proximal to the eye of the human
subject in need of prevention of age related macular degeneration.

19. The method of claim 17, wherein the eye has a sclera with an outer
scleral surface and the solid drug delivery system is placed proximal to
the outer scleral surface or within a scleral flap.

20. The method of claim 17, wherein the solid drug delivery system is
placed between the sclera and conjunctiva.

21. The method of claim 18, wherein the human subject is identified as
being at heightened risk of developing wet age-related macular
degeneration in the eye to which the solid drug delivery system is
administered.

22. The method of claim 21, wherein the human subject has dry age-related
macular degeneration in at least one eye.

23. The method of claim 21, wherein the human subject has wet age-related
macular degeneration in one eye and the solid drug delivery system is
administered to the eye without wet age-related macular degeneration.

25. A solid drug delivery system comprising a limus compound, a
polyvinylpyrrolidone, and a polyacrylate.

26. The solid drug delivery system of claim 24, wherein the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and
pharmaceutically acceptable salts and esters thereof.

27. The solid drug delivery system of claim 26 which further comprises a
polyethylene glycol.

28. The solid drug delivery system of claim 26, wherein the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers an amount of the therapeutic agent with a delivery
profile selected from the group consisting of (a) the therapeutic agent
is delivered in an amount sufficient to achieve, for a period of time of
at least 90 days following administration of the solid drug delivery
system, an average concentration of the therapeutic agent in the vitreous
of the rabbit eye equivalent to a rapamycin concentration of at least 0.1
ng/ml; and (b) the therapeutic agent is delivered in an amount sufficient
to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the retina choroid of the
rabbit eye equivalent to a rapamycin concentration of at least 0.01
ng/mg.

29. The solid drug delivery system of claim 28, wherein the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers an amount of the therapeutic agent with a delivery
profile selected from the group consisting of (a) the therapeutic agent
is delivered in an amount sufficient to achieve, for a period of time of
at least 90 days following administration of the solid drug delivery
system, an average concentration of the therapeutic agent in the vitreous
of the rabbit eye equivalent to a rapamycin concentration of at least 0.5
ng/ml; and (b) the therapeutic agent is delivered in an amount sufficient
to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the retina choroid of the
rabbit eye equivalent to a rapamycin concentration of at least 0.05
ng/mg.

30. The solid drug delivery system of claim 24, wherein the therapeutic
agent is present in an amount between 1% and 60% w/w of the drug delivery
system.

31. The solid drug delivery system of claim 24, wherein the
polyvinylpyrrolidone is present in an amount between 15% and 45% w/w of
the solid drug delivery system.

32. The solid drug delivery system of claim 24, wherein the polyacrylate
is present in an amount between 5% and 30% w/w of the solid drug delivery
system.

33. The solid drug delivery system of claim 24, wherein the polyacrylate
is a polymethacrylate.

34. The solid drug delivery system of claim 24, wherein the therapeutic
agent is present in an amount between 1% and 60% w/w of the drug delivery
system, the polyvinylpyrrolidone is present in an amount between 15% and
45% w/w of the solid drug delivery system, and the polyacrylate is
present in an amount between 5% and 30% w/w of the solid drug delivery
system.

35. The solid drug delivery system of claim 26 which comprises a backing
portion at least partially impermeable to the therapeutic agent.

36. A method of treating an ocular condition in a subject requiring
placement of an ocular device, comprising administering a formulation
comprising an anti-proliferative agent proximal to the site selected for
placement of the ocular device.

37. The method of claim 36, wherein the formulation is administered prior
to, contemporaneous with, or subsequent to placement of the ocular
device.

38. The method of claim 36, wherein the anti-proliferative agent is a
limus compound, or a pharmaceutically acceptable salt or ester thereof.

39. The method of claim 38, wherein the limus compound is rapamycin.

40. The method of claim 36, wherein the ocular device is a glaucoma
drainage device.

41. The method of claim 39, wherein the ocular device comprises a shunt,
stent, tube, membrane, valve, or combination of one or more thereof.

43. The method of claim 36, wherein the formulation is a solution,
suspension, emulsion, self-emulsifying formulation, in situ gelling
formulation, or a solid drug delivery system.

44. The method of claim 36, wherein the formulation delivers an amount of
the antiproliferative agent effective to reduce cellular proliferation
proximal to the ocular device for a period of at least about 30 days.

45. The method of claim 44, wherein the formulation delivers an amount of
the therapeutic agent effective to reduce cellular proliferation proximal
to the ocular device for a period of at least about 60 days.

46. The method of claim 45, wherein the formulation delivers an amount of
the therapeutic agent effective to reduce cellular proliferation proximal
to the ocular device for a period of at least about 90 days.

47. The method of claim 36, wherein the antiproliferative agent is
rapamycin and the ocular device is a glaucoma drainage device.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is related to and claims priority from U.S.
Provisional Patent Application Ser. No. 60/664,119 titled "DRUG DELIVERY
SYSTEMS FOR TREATMENT OF DISEASES OR CONDITIONS," filed Mar. 21, 2005,
and U.S. Provisional Patent Application Ser. No. 60/666,872 titled
"GLAUCOMA DRAINAGE DEVICES," filed Mar. 30, 2005, each of which is
incorporated herein by reference in its entirety for all purposes.

FIELD

[0002] Described herein are solid drug delivery systems to treat, prevent,
inhibit, delay onset of, or cause regression of a disease or condition by
delivery of therapeutic agents to a subject, including but not limited to
a human subject, including but not limited to the treatment of
age-related macular degeneration ("AMD") by placement of a solid drug
delivery system comprising rapamycin (sirolimus), to the eye of a
subject.

BACKGROUND

[0003] The retina of the eye contains the cones and rods that detect
light. In the center of the retina is the macula lutea, which is about
1/3 to 1/2 cm in diameter. The macula provides detailed vision,
particularly in the center (the fovea), because the cones are higher in
density. Blood vessels, ganglion cells, inner nuclear layer and cells,
and the plexiform layers are all displaced to one side (rather than
resting above the cones), thereby allowing light a more direct path to
the cones.

[0004] Under the retina are the choroid, comprising a collection of blood
vessels embedded within a fibrous tissue, and the deeply pigmented
epithelium, which overlays the choroid layer. The choroidal blood vessels
provide nutrition to the retina (particularly its visual cells).

[0005] There are a variety of retinal disorders for which there is
currently no treatment or for which the current treatment is not optimal.
Retinal disorders such as uveitis (an inflammation of the uveal tract:
iris, ciliary body, and choroid), central retinal vein occlusive diseases
(CRVO), branch retinal venous occlusion (BRVO), macular degeneration,
macular edema, proliferative diabetic retinopathy, and retinal detachment
generally are all retinal disorders that are difficult to treat with
conventional therapies.

[0006] Age-related macular degeneration (AMD) is the major cause of severe
visual loss in the United States for individuals over the age of 60. AMD
occurs in either an atrophic or less commonly an exudative form. The
atrophic form of AMD is also called "dry AMD," and the exudative form of
AMD is also called "wet AMD."

[0007] In exudative AMD, blood vessels grow from the choriocapillaris
through defects in Bruch's membrane, and in some cases the underlying
retinal pigment epithelium. Organization of serous or hemorrhagic
exudates escaping from these vessels results in fibrovascular scarring of
the macular region with attendant degeneration of the neuroretina,
detachment and tears of the retinal pigment epithelium, vitreous
hemorrhage and permanent loss of central vision. This process is
responsible for more than 80% of cases of significant visual loss in
subjects with AMD. Current or forthcoming treatments include laser
photocoagulation, photodynamic therapy, treatment with VEGF antibody
fragments, treatment with pegylated aptamers, and treatment with certain
small molecule agents.

[0008] Several studies have recently described the use of laser
photocoagulation in the treatment of initial or recurrent neovascular
lesions associated with AMD (Macular Photocoagulation Study Groups (1991)
in Arch. Ophthal. 109:1220; Arch. Ophthal. 109:1232; Arch. Ophthal.
109:1242). Unfortunately, AMD subjects with subfoveal lesions subjected
to laser treatment experienced a rather precipitous reduction in visual
acuity (mean 3 lines) at 3 months follow-up. Moreover, at two years
post-treatment treated eyes had only marginally better visual acuity than
their untreated counterparts (means of 20/320 and 20/400, respectively).
Another drawback of the procedure is that vision after surgery is
immediately worse.

[0009] Photodynamic therapy (PDT) is a form of phototherapy, a term
encompassing all treatments that use light to produce a beneficial
reaction in a subject. Optimally, PDT destroys unwanted tissue while
sparing normal tissue. Typically, a compound called a photosensitizer is
administered to the subject. Usually, the photosensitizer alone has
little or no effect on the subject. When light, often from a laser, is
directed onto a tissue containing the photosensitizer, the
photosensitizer is activated and begins destroying targeted tissue.
Because the light provided to the subject is confined to a particularly
targeted area, PDT can be used to selectively target abnormal tissue,
thus sparing surrounding healthy tissue. PDT is currently used to treat
retinal diseases such as AMD. PDT is currently the mainstay of treatment
for subfoveal choroidal neovascularization in subjects with AMD
(Photodynamic Therapy for Subfoveal Choroidal Neovascularization in Age
Related Macular Degeneration with Verteporfin (TAP Study Group) Arch
Ophthalmol. 1999 117:1329-1345.

[0010] Choroidal neovascularization (CNV) has proven to be recalcitrant to
treatment in most cases. Conventional laser treatment can ablate CNV and
help to preserve vision in selected cases not involving the center of the
retina, but this is limited to only about 10% of the cases.
Unfortunately, even with successful conventional laser photocoagulation,
the neovascularization recurs in about 50-70% of eyes (50% over 3 years
and >60% at 5 years). (Macular Photocoagulation Study Group, Arch.
Ophthalmol. 204:694-701 (1986)). In addition, many subjects who develop
CNV are not good candidates for laser therapy because the CNV is too
large for laser treatment, or the location cannot be determined so that
the physician cannot accurately aim the laser. Photodynamic therapy,
although utilized in up to 50% of new cases of subfoveal CNV has only
marginal benefits over natural history, and generally delays progression
of visual loss rather than improving vision which is already decreased
secondary to the subfoveal lesion. PDT is neither preventive or
definitive. Several PDT treatments are usually required per subject and
additionally, certain subtypes of CNV fare less well than others.

[0011] Thus, there remains a long-felt need for methods and solid drug
delivery systems that may be used to optimally prevent or significantly
inhibit choroidal neovascularization and to prevent and treat wet AMD.

[0013] Uveitis is another retinal disorder that has proven difficult to
treat using existing therapies. Uveitis is a general term that indicates
an inflammation of any component of the uveal tract. The uveal tract of
the eye consists of the iris, ciliary body, and choroid. Inflammation of
the overlying retina, called retinitis, or of the optic nerve, called
optic neuritis, may occur with or without accompanying uveitis.

[0014] Uveitis is most commonly classified anatomically as anterior,
intermediate, posterior, or diffuse. Posterior uveitis signifies any of a
number of forms of retinitis, choroiditis, or optic neuritis. Diffuse
uveitis implies inflammation involving all parts of the eye, including
anterior, intermediate, and posterior structures.

[0015] The symptoms and signs of uveitis may be subtle, and vary
considerably depending on the site and severity of the inflammation.
Regarding posterior uveitis, the most common symptoms include the
presence of floaters and decreased vision. Cells in the vitreous humor,
white or yellow-white lesions in the retina and/or underlying choroid,
exudative retinal detachments, retinal vasculitis, and optic nerve edema
may also be present in a subject suffering from posterior uveitis.

[0016] Ocular complications of uveitis may produce profound and
irreversible loss of vision, especially when unrecognized or treated
improperly. The most frequent complications of posterior uveitis include
retinal detachment; neovascularization of the retina, optic nerve, or
iris; and cystoid macular edema.

[0017] Macular edema (ME) can occur if the swelling, leaking, and hard
exudates noted in background diabetic retinopathy (BDR) occur within the
macula, the central 5% of the retina most critical to vision. Background
diabetic retinopathy (BDR) typically consists of retinal microaneurisms
that result from changes in the retinal microcirculation. These
microaneurisms are usually the earliest visible change in retinopathy
seen on exam with an ophthalmoscope as scattered red spots in the retina
where tiny, weakened blood vessels have ballooned out. The ocular
findings in background diabetic retinopathy progress to cotton wool
spots, intraretinal hemorrhages, leakage of fluid from the retinal
capillaries, and retinal exudates. The increased vascular permeability is
also related to elevated levels of local growth factors such as vascular
endothelial growth factor. The macula is rich in cones, the nerve endings
that detect color and upon which daytime vision depends. When increased
retinal capillary permeability effects the macula, blurring occurs in the
middle or just to the side of the central visual field, rather like
looking through cellophane. Visual loss may progress over a period of
months, and can be very annoying because of the inability to focus
clearly. ME is a common cause of severe visual impairment.

[0018] There have been many attempts to treat CNV and its related diseases
and conditions, as well as other conditions such as macular edema and
chronic inflammation, with pharmaceuticals. For example, use of rapamycin
to inhibit CNV and wet AMD has been described in U.S. application Ser.
No. 10/665,203, which is incorporated herein by reference in its
entirety. The use of rapamycin to treat inflammatory diseases of the eye
has been described in U.S. Pat. No. 5,387,589, titled Method of Treating
Ocular Inflammation, with inventor Prassad Kulkami, assigned to
University of Louisville Research Foundation, the contents of which is
incorporated herein in its entirety.

[0019] Particularly for chronic diseases, including those described
herein, there is a great need for long acting methods for delivering
therapeutic agents to the eye, such as to the posterior segment to treat
CNV in such diseases as AMD, macular edema, proliferative retinopathies,
and chronic inflammation. Delivery systems with extended delivery of
therapeutic agent are more comfortable and convenient for a subject, due
to a diminished frequency of ocular placement of the solid drug delivery
system.

[0020] Direct delivery of therapeutic agents to the eye rather than
systemic administration may be advantageous because the therapeutic agent
concentration at the site of action is increased relative to the
therapeutic agent concentration in a subject's circulatory system.
Additionally, therapeutic agents may have undesirable side effects when
delivered systemically to treat posterior segment disease. Thus,
localized drug delivery may promote efficacy while decreasing side
effects and systemic toxicity.

SUMMARY

[0021] The methods and solid drug delivery systems described herein allow
delivery of a therapeutic agent to a subject, including but not limited
to a human subject or to the eye of a subject. Described herein are
methods and solid drug delivery systems for delivering a variety of
therapeutic agents for the treatment, prevention, inhibition, delaying
onset of, or causing regression of a number of conditions or diseases,
including but not limited to diseases or conditions of the eye. Also
described herein are methods of administering an antiproliferative agent
proximal to an ocular device to treat a disease or condition of the eye;
in some variations the ocular device is a glaucoma drainage device.

[0022] Described herein are solid drug delivery systems comprising
rapamycin, and wherein the solid drug delivery system when placed between
the sclera and conjunctiva of a rabbit eye delivers an amount of
rapamycin with a delivery profile selected from the group consisting of
(a) the rapamycin is delivered in an amount sufficient to achieve, for a
period of time of at least 90 days following administration of the solid
drug delivery system, an average concentration of rapamycin in the
vitreous of the rabbit eye of at least 0.01 ng/ml; and (b) the rapamycin
is delivered in an amount sufficient to achieve, for a period of time of
at least 90 days following administration of the solid drug delivery
system, an average concentration of rapamycin in the retina choroid of
the rabbit eye of at least 1 pg/mg.

[0023] In some variations the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers an amount of
rapamycin with a delivery profile selected from the group consisting of
(a) the rapamycin is delivered in an amount sufficient to achieve, for a
period of time of at least 90 days following administration of the solid
drug delivery system, an average concentration of rapamycin in the
vitreous of the rabbit eye of at least 0.1 ng/ml; and (b) the rapamycin
is delivered in an amount sufficient to achieve, for a period of time of
at least 90 days following administration of the solid drug delivery
system, an average concentration of rapamycin in the retina choroid of
the rabbit eye of at least 10 pg/mg.

[0024] In some variations the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers an amount of
rapamycin with a delivery profile selected from the group consisting of
(a) the rapamycin is delivered in an amount sufficient to achieve, for a
period of time of at least 90 days following administration of the solid
drug delivery system, an average concentration of rapamycin in the
vitreous of the rabbit eye of at least 1 ng/ml; and (b) the rapamycin is
delivered in an amount sufficient to achieve, for a period of time of at
least 90 days following administration of the solid drug delivery system,
an average concentration of rapamycin in the retina choroid of the rabbit
eye of at least 100 pg/mg.

[0025] Described herein are solid drug delivery systems comprising a
therapeutic agent, wherein the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers an amount of
the therapeutic agent with a delivery profile selected from the group
consisting of (a) the the therapeutic agent is delivered in an amount
sufficient to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the vitreous of the rabbit eye
equivalent to a rapamycin concentration of at least 0.01 ng/ml; and (b)
the the therapeutic agent is delivered in an amount sufficient to
achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the retina choroid of the
rabbit eye equivalent to a rapamycin concentration of at least 1 pg/mg.
In some variations the therapeutic agent is a limus compound. In some
variations the therapeutic agent is selected from the group consisting of
rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779,
AP23841, ABT-578, cyclophilins, TAFA-93, RAD-001, temsirolimus, AP23573,
7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin,
monoester derivatives of rapamycin, diester derivatives of rapamycin,
27-oximes of rapamycin; 42-oxo analogs of rapamycin; bicyclic rapamycins;
rapamycin dimers; silyl ethers of rapamycin; rapamycin arylsulfonates,
rapamycin sulfamates, monoesters at positions 31 and 42, diesters at
positions 31 and 42, 30-demethoxy rapamycin, and pharmaceutically
acceptable salts and esters thereof. In some variations the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and
pharmaceutically acceptable salts and esters thereof.

[0026] Described herein are solid drug delivery systems comprising a
backing portion that is at least partially impermeable to the therapeutic
agent.

[0027] Described herein are solid drug delivery systems, wherein the solid
drug delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers an amount of the therapeutic agent with a delivery
profile selected from the group consisting of (a) the therapeutic agent
is delivered in an amount sufficient to achieve, for a period of time of
at least 90 days following administration of the solid drug delivery
system, an average concentration of the therapeutic agent in the vitreous
of the rabbit eye equivalent to a rapamycin concentration of at least 0.1
ng/ml; and (b) the therapeutic agent is delivered in an amount sufficient
to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the retina choroid of the
rabbit eye equivalent to a rapamycin concentration of at least 10 pg/mg.
In some variations the solid drug delivery system when placed between the
sclera and conjunctiva of a rabbit eye delivers an amount of the
therapeutic agent with a delivery profile selected from the group
consisting of (a) the therapeutic agent is delivered in an amount
sufficient to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the vitreous of the rabbit eye
equivalent to a rapamycin concentration of at least 1 ng/ml; and (b) the
therapeutic agent is delivered in an amount sufficient to achieve, for a
period of time of at least 90 days following administration of the solid
drug delivery system, an average concentration of the therapeutic agent
in the retina choroid of the rabbit eye equivalent to a rapamycin
concentration of at least 0.05 pg/mg.

[0028] Described herein are solid drug delivery systems comprising a
therapeutic agent, including but not limited to rapamycin, in an amount
between 1% and 60% w/w of the drug delivery system.

[0029] Described herein are solid drug delivery systems comprising a
polyvinylpyrrolidone in an amount between 15% and 45% w/w of the solid
drug delivery system.

[0030] Described herein are solid drug delivery systems comprising a
polyacrylate in an amount between 5% and 30% w/w of the solid drug
delivery system.

[0031] Described herein are solid drug delivery systems wherein the
therapeutic agent, including but not limited to rapamycin, is present in
an amount between 1% and 60% w/w of the drug delivery system, further
comprising a polyvinylpyrrolidone present in an amount between 15% and
45% w/w of the solid drug delivery system, and a polyacrylate present in
an amount between 5% and 30% w/w of the solid drug delivery system.

[0032] In some variations, the solid drug delivery system contains between
20 .mu.g and 4 mg of rapamycin. In some variations, the solid drug
delivery system contains between 20 .mu.g and 2.5 mg of rapamycin.

[0033] Described herein are methods for treating wet age-related macular
degeneration in a human subject, the method comprising placing a solid
drug delivery system described herein proximal to the eye of a human
subject in need of treatment of age related macular degeneration.

[0034] Described herein are methods for preventing wet age-related macular
degeneration in a human subject, the method comprising placing a solid
drug delivery system described herein proximal to the eye of the human
subject in need of prevention of age related macular degeneration. In
some variations the human subject is identified as being at heightened
risk of developing wet age-related macular degeneration in the eye to
which the solid drug delivery system is administered. In some variations
the human subject has dry age-related macular degeneration in at least
one eye. In some variations the human subject has wet age-related macular
degeneration in one eye and the solid drug delivery system is
administered to the eye without wet age-related macular degeneration.

[0035] In some variations, the eye has a sclera with an outer scleral
surface and a solid drug delivery system described herein is placed
proximal to the outer scleral surface or within a scleral flap. In some
variations, a solid drug delivery system described herein is placed
between the sclera and conjunctiva.

[0037] Described herein are solid drug delivery systems comprising a limus
compound, a polyvinylpyrrolidone, and a polyacrylate.

[0038] In some variations the therapeutic agent is selected from the group
consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus,
CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and
esters thereof.

[0039] In some variations the solid drug delivery systems described herein
further comprise a polyethylene glycol.

[0040] In some variations the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers an amount of
the therapeutic agent with a delivery profile selected from the group
consisting of (a) the therapeutic agent is delivered in an amount
sufficient to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the vitreous of the rabbit eye
equivalent to a rapamycin concentration of at least 0.1 ng/ml; and (b)
the therapeutic agent is delivered in an amount sufficient to achieve,
for a period of time of at least 90 days following administration of the
solid drug delivery system, an average concentration of the therapeutic
agent in the retina choroid of the rabbit eye equivalent to a rapamycin
concentration of at least 0.01 ng/mg.

[0041] In some variations the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers an amount of
the therapeutic agent with a delivery profile selected from the group
consisting of (a) the therapeutic agent is delivered in an amount
sufficient to achieve, for a period of time of at least 90 days following
administration of the solid drug delivery system, an average
concentration of the therapeutic agent in the vitreous of the rabbit eye
equivalent to a rapamycin concentration of at least 0.5 ng/ml; and (b)
the therapeutic agent is delivered in an amount sufficient to achieve,
for a period of time of at least 90 days following administration of the
solid drug delivery system, an average concentration of the therapeutic
agent in the retina choroid of the rabbit eye equivalent to a rapamycin
concentration of at least 0.05 ng/mg.

[0042] In some variations the excipient component comprises a solvent. The
solvent may be a liquid or a solid, either prior or subsequent to mixing
with the therapeutic agent.

[0043] In some variations the excipient component comprises a release
modifying agent.

[0044] In some variations the excipient component comprises a solubilizing
agent.

[0045] In one method, a solid drug delivery system comprising a
therapeutic agent including but not limited to rapamycin, and an
excipient component, is placed in a subject to treat, prevent, inhibit,
delay of the onset of, or cause the regression of a disease or condition
of the eye.

[0046] As described in further detail in the Detailed Description section,
the methods and solid drug delivery systems may also be used for delivery
to a subject, including but not limited to a human subject or to the eye
of a human subject of therapeutically effective amounts of rapamycin for
the treatment, prevention, inhibition, delaying of the onset of, or
causing the regression of wet AMD. In some variations, the methods and
solid drug delivery systems are used to treat wet AMD. In some
variations, the methods and solid drug delivery systems are used to
prevent wet AMD. In some variations, the methods and solid drug delivery
systems described herein are used to prevent the transition from dry AMD
to wet AMD. The methods and solid drug delivery systems may also be used
for delivery to a subject, including but not limited to a human subject
or to the eye of a subject of therapeutically effective amounts of
rapamycin for the treatment, prevention, inhibition, delaying of the
onset of, or causing the regression of CNV. In some variations, the
methods and solid drug delivery systems are used to treat CNV. The
methods and solid drug delivery systems may also be used for delivery to
a subject, including but not limited to a human subject or to the eye of
a subject of therapeutically effective amounts of rapamycin for the
treatment, prevention, inhibition, delaying of the onset of, or causing
the regression of angiogenesis in the eye. In some variations, the
methods and solid drug delivery systems are used to treat angiogenesis.
Other diseases and conditions that may be treated, prevented, inhibited,
have onset delayed, or caused to regress using rapamycin are described in
the

Diseases and Conditions Section of the Detailed Description.

[0047] As described in further detail in the Detailed Description, the
methods and solid drug delivery systems may also be used for delivery to
a subject, including but not limited to a human subject or to the eye of
a subject of therapeutically effective amounts of therapeutic agents
other than rapamycin for the treatment, prevention, inhibition, delaying
of the onset of, or causing the regression of wet AMD. In some
variations, the methods and solid drug delivery systems are used to treat
wet AMD. Therapeutic agents that may be used are described in detail in
the Therapeutic Agents section. Such therapeutic agents include but are
not limited to immunophilin binding compounds. Immunophilin binding
compounds that may be used include but are not limited to the limus
family of compounds described further in the Therapeutic Agents section
herein, including rapamycin, SDZ-RAD, tacrolimus, everolimus,
pimecrolimus, CCI-779, AP23841, ABT-578, derivatives, analogs, prodrugs,
salts and esters thereof. The methods and solid drug delivery systems may
also be used for delivery to a subject, including but not limited to a
human subject or to the eye of a subject of therapeutically effective
amounts of therapeutic agents for the treatment, prevention, inhibition,
delaying of the onset of, or causing the regression of CNV. In some
variations, the methods and solid drug delivery systems are used to treat
CNV. The methods and solid drug delivery systems may also be used for
delivery to a subject, including but not limited to a human subject or to
the eye of a subject of therapeutically effective amounts of therapeutic
agents for the treatment, prevention, inhibition, delaying of the onset
of, or causing the regression of angiogenesis in the eye. In some
variations, the methods and solid drug delivery systems are used to treat
angiogenesis. Other diseases and conditions that may be treated,
prevented, inhibited, have onset delayed, or caused to regress using
therapeutic agents other than rapamycin are described in the Diseases and
Conditions section of the Detailed Description.

[0048] The solid drug delivery systems described herein may be
biodegradable or non-biodegradable. Placement includes but is not limited
to placement of the solid drug delivery system by injection or placement
with forceps in a surgical incision, delivery by a polymer-based solid
drug delivery system, delivery by a bioadhesive solid drug delivery
system, delivery by solid drug delivery system with delayed release, and
delivery by a coated solid drug delivery system.

[0049] The solid drug delivery system may also optionally include various
means for assisting in anchoring the solid drug delivery system in place.
As one nonlimiting example, such a solid drug delivery system may include
a bioadhesive layer for placement on the outer scleral surface of the
eye. In some variations, a solid drug delivery system has a surface
containing a number of protrusions which assist in anchoring the solid
drug delivery system to the outer scleral surface of the eye. As another
nonlimiting example, a solid drug delivery system is sutured to the
sclera or other tissue.

[0050] The solid drug delivery system may also optionally be a delayed
release solid drug delivery system.

[0051] The solid drug delivery systems described herein may deliver a
therapeutic agent or agents, including but not limited to rapamycin, for
an extended period of time. One nonlimiting example of such an extended
release delivery system is a solid drug delivery system that delivers a
therapeutic agent or agents to a subject or to the eye of a subject in an
amount sufficient to maintain an amount effective to treat, prevent,
inhibit, delay of the onset of, or cause the regression of a disease or
condition in a subject for an extended period of time. In one nonlimiting
example, such a delivery system delivers the therapeutic agent for at
least about one, about two, about three, about six, about nine, or about
twelve months.

[0052] Other extended periods of release are described in the Detailed
Description.

[0053] The solid drug delivery systems described herein may also deliver a
therapeutic agent in an amount equivalent to various specified
concentrations or levels of rapamycin.

[0054] Generally, any concentration of therapeutic agent that has the
desired effect can be used. The solid drug delivery system may generally
be administered in any amount or size that has the desired effect. The
solid drug delivery systems described herein may deliver a therapeutic
agent or agents for an extended period of time. One nonlimiting example
of such an extended release delivery system is a solid drug delivery
system that delivers a therapeutic agent or agents to a subject,
including but not limited to a human subject or to the eye of a subject
in an amount sufficient to maintain an amount effective to treat,
prevent, inhibit, delay onset of, or cause regression of a disease or
condition in a subject for an extended period of time. In some
variations, the solid drug delivery system is used to treat a disease or
condition in a subject, including but not limited to a human subject. In
some variations, the solid drug delivery system delivers the therapeutic
agent for at least about one, about two, about three, about six, about
nine, or about twelve months.

[0055] In some variations, the solid drug delivery system is used to
prevent wet age-related macular degeneration for an extended period of
time. In some variations, the solid drug delivery system is used to
prevent transition of dry AMD to wet AMD for an extended period of time.
In one nonlimiting example, the solid drug delivery system delivers the
rapamycin to the vitreous, sclera, retina, choroid, macula, or other
tissues of a subject, including but not limited to a human subject in an
amount sufficient to treat, prevent, inhibit, delay onset of, or cause
regression of wet age-related macular degeneration for at least about
three, about six, about nine, or about twelve months. In some variations,
the level of rapamycin is sufficient to treat AMD. In some variations,
the level of rapamycin is sufficient to prevent onset of wet AMD. Other
extended periods of release are described in the Detailed Description.

[0056] Described herein are methods of treating an ocular condition in a
subject requiring placement of an ocular device, comprising administering
a formulation comprising an anti-proliferative agent proximal to the site
selected for placement of the ocular device. In some variations the
formulation is administered prior to, contemporaneous with, or subsequent
to placement of the ocular device. In some variations the
anti-proliferative agent is a limus compound, or a pharmaceutically
acceptable salt or ester thereof. In some variations the limus compound
is rapamycin. In some variations the ocular device is a glaucoma drainage
device. In some variations the ocular device comprises a shunt, stent,
tube, membrane, valve, or combination of one or more thereof. In some
variations the method reduces cellular proliferation proximal to the
ocular device. In some variations the formulation is a solution,
suspension, emulsion, self-emulsifying formulation, in situ gelling
formulation, or a solid drug delivery system. In some variations the
formulation delivers an amount of the antiproliferative agent effective
to reduce cellular proliferation proximal to the ocular device for a
period of at least about 30 days. In some variations the formulation
delivers an amount of the therapeutic agent effective to reduce cellular
proliferation proximal to the ocular device for a period of at least
about 60 days. In some variations the formulation delivers an amount of
the therapeutic agent effective to reduce cellular proliferation proximal
to the ocular device for a period of at least about 90 days. In some
variations the antiproliferative agent is rapamycin and the ocular device
is a glaucoma drainage device.

BRIEF DESCRIPTION OF THE DRAWINGS

[0057] FIG. 1 depicts the level of rapamycin in the vitreous (ng/ml),
retina choroid (ng/mg), and sclera (ng/mg) of rabbit eyes at 1, 14, 28,
75, 95 and 107 days after subconjunctival placement of a solid drug
delivery system made of 47.7% rapamycin, 23.25% PVP K90, 5.8% PEG 400,
and 23.25% Eudragit.

[0058] FIG. 2 depicts the level of rapamycin in the retina choroid (ng/mg)
of rabbit eyes at 1, 5, 7 and 8 days after subconjunctival placement of a
solid drug delivery system made of 10.2% rapamycin and 89.8% PVP K90.

[0059] FIG. 3 depicts the level of rapamycin in the vitreous (ng/ml) of
rabbit eyes at 1, 5, 7 and 8 days after subconjunctival placement of a
solid drug delivery system made of 10.2% rapamycin and 89.8% PVP K90.

[0060] FIG. 4 depicts the level of rapamycin in the vitreous (ng/ml),
retina choroid and sclera of rabbit eyes at 14, 42, 63 and 91 days after
subconjunctival placement of a solid drug delivery system made of 45.13%
rapamycin, 40.03% PVP K90, 9.7% Eudragit RL100, and 5.14% PEG400.

[0061] FIG. 5 depicts the level of rapamycin in the aqueous humor (ng/ml)
of rabbit eyes at 25, 35 and 37 days after subconjunctival placement of a
solid drug delivery system with a backing, wherein the solid drug
delivery system was made of 19.33% rapamycin, 21.78% PVP K90, 24.56% PEG
400, and 34.33% ethanol.

DETAILED DESCRIPTION

[0062] Described herein are solid drug delivery systems and methods
relating to delivery of therapeutic agents to a subject, including but
not limited to a human subject or to the eye of a subject. These solid
drug delivery systems and methods may be used for the treatment,
prevention, inhibition, delaying onset of, or causing regression of
diseases and conditions of the eye including but not limited to diseases
or conditions of the posterior segment, including but not limited to
choroidal neovascularization; macular degeneration; age-related macular
degeneration ("AMD"), including wet AMD and dry AMD; retinal
angiogenesis; chronic uveitis; and other retinoproliferative conditions.
In some variations, the solid drug delivery systems or methods described
herein are used for the treatment of the aforementioned diseases or
conditions of the eye.

[0063] Herein are described (1) solid drug delivery systems including
solid drug delivery systems with extended delivery of one or more
therapeutic agents, (2) the therapeutic agents that may be delivered to a
subject, including but not limited to a human subject or an eye of a
subject using the solid drug delivery systems and methods described
herein, (3) diseases and conditions that may be treated, prevented,
inhibited, onset delayed, or regression caused by delivery of the
therapeutic agents, (4) methods of treatment, (5) routes of
administration for delivery of solid drug delivery systems and methods,
(6) treatment of CNV and wet AMD by delivery of rapamycin to a subject or
to the eye of a subject using the solid drug delivery systems described
herein, and (7) administration of one or more antiproliferative agents
proximal to a glaucoma drainage device.

Solid Drug Delivery Systems for Delivery of Therapeutic Agents

[0064] In this section are described solid drug delivery systems. In some
variations the solid drug delivery systems comprise a therapeutic agent
described in the Therapeutic Agents section, including but not limited to
rapamycin. Delivery of therapeutic agents using the solid drug delivery
systems described herein may be used to treat, prevent, inhibit, delay
the onset of, or cause the regression of the diseases and conditions
described herein. The solid drug delivery systems described herein may
comprise one or more than one therapeutic agent. Other solid drug
delivery systems in addition to those explicitly described herein may be
used.

[0065] The solid drug delivery systems described herein comprise a
therapeutic agent component and an excipient component. In some
variations, the solid drug delivery systems described herein are capable
of extended delivery of a therapeutic agent to an eye of a subject. The
therapeutic agent component may comprise one or more therapeutic agents.
The excipient component may comprise one or more excipients. The
excipient component may comprise one or more solid or liquid solvents. In
some variations the solid drug delivery system further comprises one or
more solubilizing agents, surfactants, stabilizing agents, adjuvants,
release modifying agents, antioxidants, etc.

[0066] The therapeutic agent may be, for instance, between 0.05 to 99%
w/w; between 0.1 to 70%; between 1 to 50%; between 1.5 to 25%; between 5
to 20%; between 8 to 15%; between 5 to 10%; between 8 to 15%; between 1
to 5%; between 30 to 40%; between 40 to 50%; between 50 to 60%; between
60 to 70%; or between 70 to 80% w/w. By "w/w" is meant the weight of a
given component as compared to the total weight of the final formulation.

[0067] The excipient component may be, for instance, between 5 to 99.9% of
the total weight of the solid drug delivery system; between 10 to 90%;
between 5 to 50%; between 1.5 to 25%; between 5 to 20%; between 8 to 15%;
between 5 to 10%; between 8 to 15%; between 1 to 5%; between 30 to 40%;
between 40 to 50%; between 50 to 60%; between 60 to 70%; between 70 to
80%; between 80 to 90%; or between 90 to 99.9%. The solid drug delivery
systems may optionally further comprise surfactants, stabilizing agents,
adjuvants, antioxidants, etc., between 0 and 40% by weight of the total.

[0068] The term "about," as used herein, generally refers to the level of
accuracy that is obtained when the methods described herein, such as the
methods in the examples, are used. However, by "about" a certain amount
of a component of a formulation is meant 90-110% of the amount stated.

[0069] The solid drug delivery systems described herein may be used to
deliver amounts of the therapeutic agents effective for treating,
preventing, inhibiting, delaying on set of, or causing the regression of
the diseases and conditions described in the Diseases and Conditions
section. In some variations the solid drug delivery systems described
herein deliver one or more therapeutic agents over an extended period of
time.

[0070] Generally, the therapeutic agent may be formulated in any solid
drug delivery system capable of delivery of a therapeutically effective
amount of the therapeutic agent to a subject or to the eye of a subject
for the desired delivery period.

Excipients

[0071] The solid drug delivery systems described herein may comprise an
excipient component. The excipient component may comprise one or more
excipients. An "excipient," as used herein, is any substance in the solid
drug delivery system other than the therapeutic agent. Excipients may,
for instance, aid in manufacturing the solid drug delivery system, assist
in solubilizing the therapeutic agent, enhance the stability both prior
and subsequent to placement of the solid drug delivery system, modify the
delivery of the therapeutic agent to a target tissue, enhance transport
through or to a tissue, or add color and flavor to the solid drug
delivery system.

[0072] In some variations the excipient component may comprise one or more
of solvents, surfactants, stabilizing agents, adjuvants, release
modifying agents, antioxidants, etc. Note that there is overlap between
categories of excipients, such as that are solvents, stabilizers,
solubilizing agents or surfactants, and the same component can carry out
more than one role. For example, polyvinylpyrrolidone ("PVP") may be
characterized by those of skill in the art as either a stabilizing agent
or a solvent.

[0073] In some variations, the excipient component comprises a solvent
component. The solvent may comprise one or more solvents. The solvent may
be a solid or a liquid solvent. Any of the solvents described herein may
be used in the excipient component.

[0074] In some variations, the solvent is polyethylene glycol.
Polyethylene glycol is known by various names and is available in various
preparations, including but not limited to macrogols, macrogel 400,
macrogel 1500, macrogel 4000, macrogel 6000, macrogel 20000, macrogola,
breox PEG; carbowax; carbowax sentry; Hodag PEG; Lipo; Lipoxol; Lutrol E;
PEG; Pluriol E; polyoxyethylene glycol, and
.alpha.-Hydro-.omega.-hydroxy-poly(oxy-1,2-ethanediyl). In some
variations, the solvent component comprises a liquid polyethylene glycol.
In some variations, the solvent component comprises a low molecular
weight polyethylene glycol. In some variations, the solvent component
comprises PEG 300 or PEG 400.

[0075] In some variations, the solvent is substantially absent from the
solid drug delivery system after the solid drug delivery system is
prepared. As one non-limiting example, a solvent may be added to the
therapeutic agent, then during or after the processing removed. In some
variations the solvent is substantially absent from the solid drug
delivery system after its preparation, and the solid drug delivery system
is a solid drug delivery system.

[0076] In some variations, the excipient component comprises a
solubilizing agent component. The solubilizing agent component may
comprise one or more solubilizing agents. Any of the solubilizing agents
described herein may be used in the excipient component. In some
variations the solubilizing agent is a surfactant.

[0077] In some variations, the excipient component comprises a stabilizing
agent component. The stabilizing agent component may comprise one or more
plasticizing agents. Any stabilizing agents may be used in the excipient
component. In some variations, the stabilizing agent component comprises
cross-linked or non-cross-linked polyvinylpyrrolidone (PVP).

[0078] In some variations, the excipient is a polyvinylpyrrolidone.
Polyvinylpyrrolidone is known by various names and is available in
various preparations, including but not limited to povidone, povidonum,
kollidon; plasdone; poly[1-(2-oxo-1-pyrrolidinyl)ethylene]; polyvidone;
PVP; 1-vinyl-2-pyrrolidinone polymer, and 1-Ethenyl-2-pyrrolidinone
homopolymer. In some variations, the PVP is PVP K-90.

[0079] In some variations, the excipient component comprises a release
modifying agent. In some variations, the release modifying agent is a
film-forming polymer component. The film-forming polymer component may
comprise one or more film-forming polymers. Any film-forming polymer may
be used in the excipient component. In some variations, the film-forming
polymer component comprises a water insoluble film forming polymer. In
some variations, the film-forming polymer component comprises an acrylic
polymer, including but not limited to polymethacrylate, including but not
limited to Eudragit RL.

[0081] In order to determine whether a potential agent may be used as an
excipient in the solid drug delivery systems described herein, one of
skill in the art may mix any of the therapeutic agents described herein,
including but not limited to rapamycin, with any of the potential
excipient components or agents as described herein, or any other
excipient known in the art. The resulting solid drug delivery system may
be placed in an appropriate animal model, including but not limited to
placement in or proximal to the sclera or the area between the sclera and
the conjunctiva of a rabbit eye, and average levels of therapeutic agent
may monitored for an extended period of time.

Solvents for Therapeutic Agents

[0082] One solid drug delivery system that may be used is a solid drug
delivery system comprising a solvent component.

[0083] In some variations any solvent may be used in which the therapeutic
agent dissolves. In some variations the solvent is aqueous. In some
variations the solvent is non-aqueous. An "aqueous solvent" is a solvent
that contains at least about 50% water.

[0084] In some variations the solvent is a solid solvent and the resulting
solution is a solid solution. In some variations, any solid solvent is
used wherein the therapeutic agent, when combined with the solvent and
placed in the subconjunctiva of a rabbit eye, gives extended release of
the therapeutic agent as described herein. In some variations, the
solvent and the therapeutic agent are mixed by blending, mixing,
mechanical manipulation, precipitation, or some other method used in the
art.

[0085] Generally, any concentration of therapeutic agent that has the
desired effect can be used. The solvent component may be a single solvent
or may be a mixture of solvents. Solvents and types of solutions are well
known to those versed in such drug delivery technologies. See for
example, Remington: The Science and Practice of Pharmacy, Twentieth
Edition, Lippincott Williams & Wilkins; 20th edition (Dec. 15, 2000);
Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Eighth
Edition, Lippincott Williams & Wilkins (August 2004); Strickley,
Solubilizing Excipeints in Oral and Injectable Formulations,
Pharmaceutical Research, Vol. 21, No. 2, February 2004.

[0086] As noted previously, some solvents may also serve as solubilizing
agents.

[0087] The solvent may remain in the solid drug delivery system or be
removed after processing of the solid drug delivery system or placement
of the solid drug delivery system in or proximal to the eye of the
subject.

[0088] Solvents that may be used include but are not limited to DMSO,
ethanol, methanol, isopropyl alcohol; castor oil, propylene glycol,
polysorbate 80, benzyl alcohol, triacetin, diacetin, corn oil, ethyl
lactate, glycerol formal, ethoxy diglycol (Transcutol, Gattefosse),
tryethylene glycol dimethyl ether (Triglyme), dimethyl isosorbide (DMI),
.gamma.-butyrolactone, N-Methyl-2-pyrrolidinone (NMP), and polyglycolated
capryl glyceride (Labrasol, Gattefosse) combinations of any one or more
of the foregoing, or analogs or derivatives of any one or more of the
foregoing.

[0089] In some variations, the solvent is glycerin, dimethylsulfoxide,
N-methylpyrrolidone, dimethyl acetamide (DMA), dimethyl formamide,
glycerol formal, ethoxy diglycol, triethylene glycol dimethyl ether,
triacetin, diacetin, corn oil, acetyl triethyl citrate (ATC), ethyl
lactate, polyglycolated capryl glyceride, .gamma. butyrolactone, dimethyl
isosorbide, benzyl alcohol, ethanol, isopropyl alcohol, polyethylene
glycol of various molecular weights, including but not limited to PEG 300
and PEG 400, or propylene glycol, combinations of any one or more of the
foregoing, or analogs or derivatives of any one or more of the foregoing.

[0090] In some variations, the solvent is a polyethylene glycol.
Polyethylene glycol is known by various names and is available in various
preparations, including but not limited to macrogels, macrogel 400,
macrogel 1500, macrogel 4000, macrogel 6000, macrogel 20000, macrogola,
breox PEG; carbowax; carbowax sentry; Hodag PEG; Lipo; Lipoxol; Lutrol E;
PEG; Pluriol E; polyoxyethylene glycol, and
.alpha.-Hydro-.omega.-hydroxy-poly(oxy-1,2-ethanediyl).

[0091] In some variations the polyethylene glycol is a liquid PEG, and is
one or more of PEG 300 or PEG 400.

[0092] Other solvents include an amount of a C.sub.6-C.sub.24 fatty acid
sufficient to solubilize a therapeutic agent.

[0093] Phospholipid solvents may also be used, such as lecithin,
phosphatidylcholine, or a mixture of various diglycerides of stearic,
palmitic, and oleic acids, linked to the choline ester of phosphoric
acid; hydrogenated soy phosphatidylcholine (HSPC),
distearoylphosphatidylglycerol (DSPG),
L-.alpha.-dimyristoylphosphatidylcholine (DMPC),
L-.alpha.-dimyristoylphosphatidylglycerol (DMPG).

[0094] Further examples of solvents include, for example, components such
as alcohols, propylene glycol, polyethylene glycol of various molecular
weights, propylene glycol esters, propylene glycol esterified with fatty
acids such as oleic, stearic, palmic, capric, linoleic, etc; medium chain
mono-, di-, or triglycerides, long chain fatty acids, naturally occurring
oils, and a mixture thereof. The oily components for the solvent system
include commercially available oils as well as naturally occurring oils.
The oils may further be vegetable oils or mineral oils. The oils can be
characterized as non-surface active oils, which typically have no
hydrophile lipophile balance value. Commercially available substances
comprising medium chain triglycerides include, but are not limited to,
Captex 100, Captex 300, Captex 355, Miglyol 810, Miglyol 812, Miglyol
818, Miglyol 829, and Dynacerin 660. Propylene glycol ester compositions
that are commercially available encompass Captex 200 and Miglyol 840, and
the like. The commercial product, Capmul MCM, comprises one of many
possible medium chain mixtures comprising monoglycerides and
diglycerides.

[0095] Other solvents include naturally occurring oils such as peppermint
oil, and seed oils. Exemplary natural oils include oleic acid, castor
oil, safflower seed oil, soybean oil, olive oil, sunflower seed oil,
sesame oil, and peanut oil. Soy fatty acids may also be used. Examples of
fully saturated non-aqueous solvents include, but are not limited to,
esters of medium to long chain fatty acids (such as fatty acid
triglycerides with a chain length of about C.sub.6 to about C.sub.24).
Hydrogenated soybean oil and other vegetable oils may also be used.
Mixtures of fatty acids may be split from the natural oil (for example
coconut oil, palm kernel oil, babassu oil, or the like) and refined. In
some embodiments, medium chain (about C.sub.8 to about C.sub.12)
triglycerides, such as caprilyic/capric triglycerides derived from
coconut oil or palm seed oil, may be used. Medium chain mono- and
diglycerides may also be used. Other fully saturated non-aqueous solvents
include, but are not limited to, saturated coconut oil (which typically
includes a mixture of lauric, myristic, palmitic, capric and caproic
acids), including those sold under the Miglyol.TM. trademark from Huls
and bearing trade designations 810, 812, 829 and 840). Also noted are the
NeoBee.TM. products sold by Drew Chemicals. Non-aqueous solvents include
isopropyl myristate. Examples of synthetic oils include triglycerides and
propylene glycol diesters of saturated or unsaturated fatty acids having
6 to 24 carbon atoms such as, for example hexanoic acid, octanoic
(caprylic), nonanoic (pelargonic), decanoic (capric), undecanoic, lauric,
tridecanoic, tetradecanoic (myristic), pentadecanoic, hexadecanoic
(palmitic), heptadecanoic, octadecanoic (stearic), nonadecanoic,
heptadecanoic, eicosanoic, heneicosanoic, docosanoic and lignoceric
acids, and the like. Examples of unsaturated carboxylic acids include
oleic, linoleic and linolenic acids, and the like. The non-aqueous
solvent can comprise the mono-, di- and triglyceryl esters of fatty acids
or mixed glycerides and/or propylene glycol mono- or diesters wherein at
least one molecule of glycerol has been esterified with fatty acids of
varying carbon atom length. A non-limiting example of a "non-oil" useful
as a solvent is polyethylene glycol.

[0097] Polyvinyl pyrrolidone (PVP), cross-linked or not, may also be used
as a solvent. Further solvents include but are not limited to
C.sub.6-C.sub.24 fatty acids, oleic acid, Imwitor 742, Capmul, F68, F68
(Lutrol), PLURONICS including but not limited to PLURONICS F108, F127,
and F68, Poloxamers, Jeffamines), Tetronics, F127; cyclodextrins such as
.alpha.-cyclodextrin, .beta.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin, sulfobutylether-.beta.-cyclodextrin
(Captisol); carboxymethylcellulose (CMC), polysorbitan 20, Cavitron,
polyethylene glycol of various molecular weights including but not
limited to PEG 300 and PEG 400.

[0098] Beeswax and d-.alpha.-tocopherol (Vitamin E) may also be used as
solvents.

[0099] Solvents for use in the solid drug delivery systems can be
determined by a variety of methods known in the art, including but not
limited to (1) theoretically estimating their solubility parameter values
and choosing the ones that match with the therapeutic agent, using
standard equations in the field; and (2) experimentally determining the
saturation solubility of therapeutic agent in the solvents, and choosing
the ones that exhibit the desired solubility.

Solubilization of Rapamycin

[0100] Where the therapeutic agent is rapamycin, solvents that may be used
for making solid drug delivery systems comprising rapamycin include but
are not limited to any solvent described herein, including but not
limited to any one or more of DMSO, glycerin, ethanol, methanol,
isopropyl alcohol; castor oil, propylene glycol, polyvinylpropylene,
glycerin, polysorbate 80, benzyl alcohol, dimethyl acetamide (DMA),
dimethyl formamide (DMF), glycerol formal, ethoxy diglycol (Transcutol,
Gattefosse), tryethylene glycol dimethyl ether (Triglyme), dimethyl
isosorbide (DMI), .gamma.-butyrolactone, N-Methyl-2-pyrrolidinone (NMP),
polyethylene glycol of various molecular weights, including but not
limited to PEG 300 and PEG 400, and polyglycolated capryl glyceride
(Labrasol, Gattefosse).

[0102] Other methods that may be used to dissolve rapamycin are described
in Solubilization of Rapamycin, P. Simamora et al. Int'l J. Pharma 213
(2001) 25-29, the contents of which is incorporated herein in its
entirety.

[0103] Many other solvents are possible. Those of ordinary skill in the
art will find it routine to identify which solvents may be used for
rapamycin.

Release-Modifying Agents

[0104] In some variations, the release modifying agent accelerates the
release rate of the therapeutic agent from the solid drug delivery
system. In some variations, the release modifying agent slows the release
rate of the therapeutic agent from the solid drug delivery system.

[0105] In some variations, the release modifying agent is a film-forming
polymer component. The film-forming polymer component may comprise one or
more film-forming polymers. Any film-forming polymer may be used in the
excipient component. In some variations, the film-forming polymer
component comprises a water insoluble film forming polymer. In some
variations, the film-forming polymer component comprises an acrylic
polymer.

[0107] The excipient component of the solid drug delivery systems
described herein may comprise stabilizers. Stabilizers that may be used
in the solid drug delivery systems described herein include but are not
limited to agents that (1) improve the compatibility of excipients with
the encapsulating materials such as gelatin, (2) improve the stability
(e.g. prevent crystal growth) of a therapeutic agent including but not
limited to rapamycin and/or rapamycin derivatives, and/or (3) improve
solid drug delivery system stability.

[0108] Stabilizers include but are not limited to fatty acids, fatty
alcohols, alcohols, long chain fatty acid esters, long chain ethers,
hydrophilic derivatives of fatty acids, polyvinylpyrrolidones,
polyvinylethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers,
moisture-absorbing polymers, and combinations thereof. Amide analogues of
the above stabilizers can also be used. The chosen stabilizer may change
the hydrophobicity of the solid drug delivery system (e.g. oleic acid,
waxes), or improve the mixing of various components in the solid drug
delivery system (e.g. ethanol), control the moisture level in the formula
(e.g. PVP), control the mobility of the phase (substances with melting
points higher than room temperature such as long chain fatty acids,
alcohols, esters, ethers, amides etc. or mixtures thereof; waxes), and/or
improve the compatibility of the formula with encapsulating materials
(e.g. oleic acid or wax). Some of these stabilizers may be used as
solvents/co-solvents (e.g. ethanol). Stabilizers may be present in
sufficient amount to inhibit the therapeutic agent's (such as
rapamycin's) crystallization.

[0110] In some variations, the stabilizing agent is polyvinylpyrrolidone.
Polyvinylpyrrolidone is known by various names and is available in
various preparations, including but not limited to povidone, povidonum,
kollidon; plasdone; poly[1-(2-oxo-1-pyrrolidinyl)ethylene]; polyvidone;
PVP; 1-vinyl-2-pyrrolidinone polymer, and 1-Ethenyl-2-pyrrolidinone
homopolymer.

Gelling Agents

[0111] The excipient component of the solid drug delivery systems
described herein may comprise a gelling agent that alters the texture of
the final solid drug delivery system through formation of a gel.

[0113] The excipient component of the solid drug delivery systems
described herein may comprise one or more adjuvants appropriate for the
indicated route of administration or placement. Adjuvants with which the
therapeutic agent may be admixed with include but are not limited to
lactose, sucrose, starch powder, cellulose esters of alkanoic acids,
stearic acid, talc, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium
alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol. When a
solubilized solid drug delivery system is required the therapeutic agent
may be in a solvent or solubilizing agent including but not limited to
polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal
solutions, methanol, ethanol, DMSO, corn oil, peanut oil, cottonseed oil,
sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and
modes of administration are well known in the pharmaceutical art and may
be used in the practice of the methods and solid drug delivery systems
described herein. The carrier or diluent may include time delay material,
such as glyceryl monostearate or glyceryl distearate alone or with a wax,
or other materials well known in the art. The solid drug delivery system
for use as described herein may also comprise gel formulations, erodible
and non-erodible polymers, micropsheres, and liposomes.

[0114] Other adjuvants and excipients that may be used include but are not
limited to C8-C10 fatty acid esters such as softigen 767, polysorbate 80,
Pluronics, Tetronics, Miglyol, and Transcutol.

Additives and Diluents

[0115] The excipient component of the solid drug delivery systems
described herein may comprise additives or diluents, such as those
normally utilized in the pharmaceutical arts. These include thickening,
granulating, dispersing, flavoring, sweetening, coloring, and stabilizing
agents, including pH stabilizers, other excipients, anti-oxidants (e.g.,
tocopherol, BHA, BHT, TBHQ, tocopherol acetate, ascorbyl palmitate,
ascorbic acid propyl gallate, and the like), preservatives (e.g.,
parabens), and the like. Exemplary preservatives include, but are not
limited to, benzylalcohol, ethylalcohol, benzalkonium chloride, phenol,
chlorobutanol, and the like. Some useful antioxidants provide oxygen or
peroxide inhibiting agents for the solid drug delivery system and
include, but are not limited to, butylated hydroxytoluene,
butylhydroxyanisole, propyl gallate, ascorbic acid palmitate,
.alpha.-tocopherol, and the like. Thickening agents, such as lecithin,
hydroxypropylcellulose, aluminum stearate, and the like, may improve the
texture of the solid drug delivery system.

[0116] In addition, a viscous polymer may be added to the suspension,
assisting the localization in the eye, including but not limited to the
sclera, and ease of placement and handling. In some uses of the solid
drug delivery system, a pocket in the sclera may be surgically formed to
receive an injection or placement of the solid drug delivery systems.
Particles of therapeutic agent substance for forming a suspension can be
produced by known methods including but not limited to via ball milling,
for example by using ceramic beads. For example, a Cole Parmer ball mill
such as Labmill 8000 may be used with 0.8 mm YTZ ceramic beads available
from Tosoh or Norstone Inc.

[0117] Many other solvents are possible. Those of ordinary skill in the
art will find it routine to identify solvents for rapamycin given the
teachings herein.

Solubilizing Agents

[0118] The excipient component of the solid drug delivery systems
described herein may comprise one or more solubilizing agents. Generally,
any solubilizing agent or combination of solubilizing agents may be used
in the solid drug delivery systems described herein.

[0119] In some variations, the solubilizing agent is a surfactant or
combination of surfactants. Many solubilizing agents and surfactants are
possible. In some variations, combinations of solubilizing agents or
surfactants, including but not limited to combinations of various types
of solubilizing agents or surfactants, may also be used. For instance,
surfactants which are nonionic, anionic (i.e. soaps, sulfonates),
cationic (i.e. CTAB), zwitterionic, polymeric or amphoteric may be used.

[0120] In some variations, a solubilizing agent or surfactant for use in
the solid drug delivery systems described herein is determined by mixing
a putative solubilizing agent or surfactant with a solid drug delivery
system as described herein, and observing the characteristics of the
solid drug delivery system after placement in a subject.

[0121] Examples of surfactants include but are not limited to fatty acid
esters or amides or ether analogues, or hydrophilic derivatives thereof;
monoesters or diesters, or hydrophilic derivatives thereof; or mixtures
thereof; monoglycerides or diglycerides, or hydrophilic derivatives
thereof; or mixtures thereof; mixtures having enriched mono- or/and
diglycerides, or hydrophilic derivatives thereof; surfactants with a
partially derivatized with a hydrophilic moiety; monoesters or diesters
or multiple-esters of other alcohols, polyols, saccharides or
oligosaccharides or polysaccharides, oxyalkylene oligomers or polymers or
block polymers, or hydrophilic derivatives thereof, or the amide
analogues thereof; fatty acid derivatives of amines, polyamines,
polyimines, aminoalcohols, aminosugars, hydroxyalkylamines,
hydroxypolyimines, peptides, polypeptides, or the ether analogues
thereof.

[0122] Hydrophilic Lipophilic Balance ("HLB") is an expression of the
relative simultaneous attraction of a surfactant for water and oil (or
for the two phases of the emulsion system being considered).

[0123] Surfactants are characterized according to the balance between the
hydrophilic and lipophilic portions of their molecules. The
hydrophilic-lipophilic balance (HLB) number indicates the polarity of the
molecule in an arbitrary range of 1-40, with the most commonly used
emulsifiers having a value between 1 and 20. The HLB increases with
increasing hydrophilicity.

[0125] The surfactant component may be selected from compounds having at
least one ether formed from at least 1 to 100 ethylene oxide units and at
least one fatty alcohol chain having from at least 12 to 22 carbon atoms;
compounds having at least one ester formed from at least about 1 to 100
ethylene oxide units and at least one fatty acid chain having from at
least 12 to 22 carbon atoms; compounds having at least one ether, ester
or amide formed from at least 1 to 100 ethylene oxide units and at least
one vitamin or vitamin derivative; and combinations thereof consisting of
no more than two surfactants.

[0128] In some variations, surfactants having an HLB lower than 10 are
used. Such surfactants may optionally be used in combination with other
surfactants as co-surfactants. Examples of some surfactants, mixtures,
and other equivalent compositions having an HLB less than or equal to 10
are propylene glycols, glyceryl fatty acids, glyceryl fatty acid esters,
polyethylene glycol esters, glyceryl glycol esters, polyglycolyzed
glycerides and polyoxyethyl steryl ethers. Propylene glycol esters or
partial esters form the composition of commercial products, such as
Lauroglycol FCC, which contains propylene glycol laureate. The
commercially available excipient Maisine 35-1 comprises long chain fatty
acids, for example glyceryl linoleate. Products, such as Acconon E, which
comprise polyoxyethylene stearyl ethers, may also be used. Labrafil M
1944 CS is one example of a surfactant wherein the composition contains a
mixture of glyceryl glycol esters and polyethylene glycol esters.

Solubilizing Agents for Rapamycin

[0129] Many solubilizing agents or surfactants may be used for rapamycin,
including but not limited to any solubilizing agent described herein,
including but not limited to the solubilizing agents in this section.

[0130] In some variations the solubilizing agent is a surfactant.
Nonlimiting examples of surfactants that may be used for rapamycin
include but are not limited to surfactants with an HLB greater than 10,
11, 12, 13 or 14. One nonlimiting example is Cremophor EL. In some
variations, the surfactant may be a polymeric surfactant including but
not limited to PLURONICS F108, F127, and F68, and Tetronics. As noted
above, some solubilizing agents may also serve as solvents. Those of
ordinary skill in the art will find it routine to identify which
surfactants may be used for rapamycin given the teachings herein.

Viscosity Modifying Agents

[0131] The solid drug delivery systems described herein may be placed in
combination with or further comprise a viscosity modifying agent.

[0132] One exemplary viscosity modifying agent that may be used is
hyaluronic acid. Hyaluronic acid is a glycosaminoglycan. It is made of a
repetitive sequence of glucuronic acid and glucosamine. Hyaluronic acid
is present in many tissues and organs of the body, and contributes to the
viscosity and consistency of such tissues and organs. Hyaluronic acid is
present in the eye, including the vitreous of the eye, and along with
collagen contributes to the viscosity thereof. The solid drug delivery
systems described herein may further comprise or be administered with
hyaluronic acid.

[0135] The formulations described herein may further comprise various
other components such as stabilizers, for example. Stabilizers that may
be used in the formulations described herein include but are not limited
to agents that will (1) improve the compatibility of excipients with the
encapsulating materials such as gelatin, (2) improve the stability (e.g.
prevent crystal growth of a therapeutic agent such as rapamycin) of a
therapeutic agent such as rapamycin and/or rapamycin derivatives, and/or
(3) improve formulation stability. Note that there is overlap between
components that are stabilizers and those that are solvents, solubilizing
agents or surfactants, and the same component can carry out more than one
role.

[0136] Stabilizers may be selected from fatty acids, fatty alcohols,
alcohols, long chain fatty acid esters, long chain ethers, hydrophilic
derivatives of fatty acids, polyvinylpyrrolidones, polyvinylethers,
polyvinyl alcohols, hydrocarbons, hydrophobic polymers,
moisture-absorbing polymers, and combinations thereof. Amide analogues of
the above stabilizers can also be used. The chosen stabilizer may change
the hydrophobicity of the formulation (e.g. oleic acid, waxes), or
improve the mixing of various components in the formulation (e.g.
ethanol), control the moisture level in the formula (e.g. PVP), control
the mobility of the phase (substances with melting points higher than
room temperature such as long chain fatty acids, alcohols, esters,
ethers, amides etc. or mixtures thereof; waxes), and/or improve the
compatibility of the formula with encapsulating materials (e.g. oleic
acid or wax). Some of these stabilizers may be used as
solvents/co-solvents (e.g. ethanol). Stabilizers may be present in
sufficient amount to inhibit the therapeutic agent's (such as
rapamycin's) crystallization.

[0138] The therapeutic agents for use as described herein, such as
rapamycin, may be subjected to conventional pharmaceutical operations,
such as sterilization and compositions containing the therapeutic agent
may also contain conventional adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifiers, buffers etc. The therapeutic
agents may also be formulated with pharmaceutically acceptable excipients
for clinical use to produce a solid drug delivery system.

[0139] The therapeutic agents may be used to prepare a medicament to
treat, prevent, inhibit, delay onset, or cause regression of any of the
conditions described herein. In some variations, one or more therapeutic
agents are used to prepare a medicament to treat any of the conditions
described herein. In some variations, one or more therapeutic agents are
used to prepare a medicament to prevent any of the conditions described
herein.

[0140] A solid drug delivery system containing a therapeutic agent such as
rapamycin may contain one or more adjuvants appropriate for the indicated
route of administration. Adjuvants with which the therapeutic agent may
be admixed with include but are not limited to lactose, sucrose, starch
powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium
stearate, magnesium oxide, sodium and calcium salts of phosphoric and
sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine,
and/or polyvinyl alcohol. When a solubilized formulation is required the
therapeutic agent may be in a solvent including but not limited to
polyethylene glycol of various molecular weights, propylene glycol,
carboxymethyl cellulose colloidal solutions, methanol, ethanol, DMSO,
corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or
various buffers. Other adjuvants and modes of administration are well
known in the pharmaceutical art and may be used in the practice of the
methods and solid drug delivery systems described herein. The carrier or
diluent may include time delay material, such as glyceryl monostearate or
glyceryl distearate alone or with a wax, or other materials well known in
the art. The formulations for use as described herein may also include
gel formulations, erodible and non-erodible polymers, microspheres, and
liposomes. Other adjuvants and excipients that may be used include but
are not limited to C.sub.8-C.sub.10 fatty acid esters such as softigen
767, polysorbate 80, PLURONICS, Tetronics, Miglyol, and Transcutol.

[0141] Additives and diluents normally utilized in the pharmaceutical arts
can optionally be added to the solid drug delivery systems described
herein. These include thickening, granulating, dispersing, flavoring,
sweetening, coloring, and stabilizing agents, including pH stabilizers,
other excipients, anti-oxidants (e.g., tocopherol, BHA, BHT, TBHQ,
tocopherol acetate, ascorbyl palmitate, ascorbic acid propyl gallate, and
the like), preservatives (e.g., parabens), and the like. Exemplary
preservatives include, but are not limited to, benzylalcohol,
ethylalcohol, benzalkonium chloride, phenol, chlorobutanol, and the like.
Some useful antioxidants provide oxygen or peroxide inhibiting agents for
the formulation and include, but are not limited to, butylated
hydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid
palmitate, .alpha.-tocopherol, and the like. Thickening agents, such as
lecithin, hydroxypropylcellulose, aluminum stearate, and the like, may
improve the texture of the formulation.

[0142] In some variations, the therapeutic agent is rapamycin, and the
rapamycin is formulated as rapamune in solid form. In some variations,
the rapamune is formulated as an oral dosage.

[0143] In addition, a viscous polymer may be added to the suspension,
assisting the localization and ease of placement and handling. In some
uses of the solid drug delivery systems, a pocket in the sclera may be
surgically formed for placement of the solid drug delivery system. The
hydrogel structure of the sclera can act as a rate-controlling membrane.

[0144] The solid drug delivery systems may conveniently be presented in
unit dosage form and may be prepared by conventional pharmaceutical
techniques. Such techniques include the step of bringing into association
the therapeutic agent and the pharmaceutical carrier(s) or excipient(s).
The formulations may be prepared by uniformly and intimately bringing
into associate the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.

[0145] In some variations, the formulations described herein are provided
in one or more unit dose forms, wherein the unit dose form contains an
amount of a solid drug delivery system described herein that is effective
to treat or prevent the disease or condition for which it is being
administered. In some variations, the solid drug delivery systems
described herein are provided in one or more unit dose forms, wherein the
unit dose form contains an amount of a rapamycin formulation described
herein that is effective to treat or prevent the disease or condition for
which it is being administered for a period of time.

[0146] In a further aspect, provided herein are kits comprising one or
more unit dose forms as described herein. In some embodiments, the kit
comprises one or more of packaging and instructions for use to treat one
or more diseases or conditions, including but not limited to the diseases
or conditions described herein. In some embodiments, the kit comprises
any of one or more unit dose forms described herein in one or more sealed
vessels or sealed packaging. In some embodiments, the kit comprises any
of one or more sterile unit dose forms.

[0147] In some variations, the unit dose form is in a container, including
but not limited to a sterile sealed container or packaging. In some
variations the container is a vial, ampule, or low volume applicator.

[0148] Described herein are kits comprising one or more unit dose forms
comprising one or more solid drug delivery systems. In some variations
the kit comprises one or more containers with instructions for its use.
In some variations a kit comprises one or more solid drug delivery
systems in a container or packaging, wherein the solid drug delivery
system comprises rapamycin, and the kit further comprises instructions
for use of the solid drug delivery system in treating a disease or
condition of the eye. In some variations, the solid drug delivery system
is in a container and the container is in a secondary packaging.

Backed Solid Drug Delivery Systems

[0149] In some variations the solid delivery systems described herein
comprise a backing. In some variations the backing is bioerodible. In
some variations the backing is nonbioerodible. In some variations the
backing is a combination of one or more bioerodible and one or more
nonbioerodible materials.

[0150] In some variations, the solid drug delivery systems with a backing
are designed to promote diffusion in a direction of choice.

[0151] In some variations a backed solid delivery system described herein
includes an erodible implant, such as a disk, cylinder, fiber, or film
comprising the active therapeutic agent, and a backing made of an
erodible polymer that contains little or no therapeutic agent. The choice
of the second erodible polymer can be such that elution of therapeutic
agent from the implant in the direction of the second polymer is blocked
or slowed, allowing for the therapeutic agent to be delivered primarily
in one direction.

[0152] In some variations, the backing layer is at least partially
impermeable to the therapeutic agent. By "at least partially permeable"
is meant that the rate of the therapeutic agent exiting the drug delivery
system through the backing is lower than the rate of the therapeutic
agent exiting the drug delivery system through the portion without the
backing.

[0153] In some variations, the backing layer is substantially impermeable
to the therapeutic agent. In some variations, a non-erodible polymer is
used as the blocking layer, and the backing layer is removed some period
of time after placement in the subject.

[0154] As used herein, "substantially impermeable" means that a clinically
insignificant amount of therapeutic agent passes through the
substantially impermeable barrier. In some variations, the substantially
impermeable barrier is for all practical purposes impermeable to the
therapeutic agent.

[0155] In some variations of a solid drug delivery system with a backing,
a suture is sandwiched between the solid drug delivery system and the
backing to allow the structure to remain securely affixed to the sclera
via the suture. In some variations the backing allows an amount of the
therapeutic agent through that does not cause local toxic effects in the
subject to which the solid drug delivery system is administered.

[0156] Generally, the backing can be made of any material that diminishes
diffusion of the therapeutic agent into the tissues proximal to the
backing as compared to diffusion into such tissues in the absence of the
backing. In some variations the backing is not completely impermeable to
the therapeutic agent but has such disparity of diffusion thereto that
for practical purposes the vast majority of the drug elutes toward the
scleral surface. The backing material may be impermeable or substantially
impermeable to the therapeutic agent or may be semi-permeable or
permeable to the therapeutic agent. In one backed polymer implant, the
material of the therapeutic agent-containing solid drug delivery system
and the backing are the same, and the concentration of the therapeutic
agent in the therapeutic agent containing polymer is greater than the
concentration in the backing. In one such implant, the backing initially
contains substantially no therapeutic agent.

[0157] In some variations the backing is shaped and sized to hold a solid
drug delivery system and reside in an ocular site. In some variations,
the backing is in the shape of a thin, shallow saucer or cup. In some
variations, the backing is made of a thermoplastic. In some variations,
the backing is made of a polyetheretherketone (PEEK), including but not
limited to Victrex K90.

[0158] In some variations, a formulation is prepared and placed in a
backing before it has become solid; by way of nonlimiting example, the
formulation is placed in a backing before one or more solvents has been
evaporated off. Such variations may include but are not limited to those
formulations shown in Table 2. Some formulations, prior to drying, are
generally but need not be suspensions.

[0159] In some variations, the formulation is allowed to dry prior to
placement in the subject. In some variations, the formulation is not dry
upon placement in the subject.

Delivery by Solid Drug Delivery System with Delayed Release

[0160] One solid drug delivery system that may be used to deliver the
therapeutic agent is a delayed release solid drug delivery system.

[0161] In one solid drug delivery system, the onset of therapeutic agent
release is delayed for a period of time after the solid drug delivery
system insertion into the eye. This delay allows for example, for time
for the wound caused by the insertion of the solid drug delivery system
to heal prior to therapeutic agent delivery. Such a delay is advantageous
when the therapeutic agent itself inhibits wound healing. For example,
therapeutic agents that inhibit fibroblastic proliferation, such as
rapamycin, will inhibit wound healing. In one such delayed release solid
drug delivery system that may be used, therapeutic agent release is
delayed by coating the solid drug delivery system containing the
therapeutic agent with a polymer that contains no or a lesser amount of a
therapeutic agent but that will erode during a predetermined time. Thus,
therapeutic agent release is delayed until a substantial portion of the
polymer coating has eroded away. As used herein, a "substantial portion"
of a substance refers to in excess of 80% of the substance. The polymer
coating may be substantially impermeable to the therapeutic agent.

[0162] Given the teachings herein, one versed in delayed release
technology will be able to identify other solid drug delivery systems
that may be used to achieve the delayed release described herein.

[0163] Depending on the therapeutic agent being delivered and/or the
diseases and conditions being treated or prevented this period of delay
before delivery of the therapeutic agent commences may be 1 hour, 6
hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,
7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 21
days, 28 days, 35 days, or 42 days. Other delay periods may be possible.
Delayed release systems that may be used are known to people versed in
the technology, and includes but is not limited to the use of a coating
or reservoir.

Delivery by a Bioadhesive Solid Drug Delivery System

[0164] One delivery system that may be used is a solid drug delivery
system in which the therapeutic agent is delivered by placement of a
solid drug delivery system that includes a bioadhesive surface.

[0165] The bioadhesive surface of the solid drug delivery system allows
the solid drug delivery system to be secured in place by adhesion to a
biomaterial in the ocular region, including but not limited to adhesion
to the outer scleral surface. The bioadhesive solid drug delivery system
may be made of a bioadhesive polymer material or may be made of a
non-bioadhesive polymer material that is coated with a bioadhesive
material to form the bioadhesive surface. The preparation of solid drug
delivery systems with bioadhesive surfaces is well known to those versed
in the technology. See, for example, Bioadhesive any phase-change
polymers for ocular drug delivery, J. Robinson et al., Advanced Drug
Delivery Review, 16 (1995) 45-50, the contents of which is incorporated
herein in its entirety.

[0167] The bioadhesive polymers may be mixed with suitable plasticizers to
obtain a flexible film. Plasticizers that may be used include but are not
limited to Propylene glycol, polypropylene glycol, polyethylene glycol,
glycerol, glycerol esters (eg. glycerol monololeate), and esters of
propylene glycol (eg. propylene glycol monolaurate), and water.

[0168] The bioadhesive polymers may be mixed with suitable wetting agents
at a very low concentrations to improve surface contact when a
bioadhesive solid drug delivery system is placed on the tissue: Wetting
agents that may be used include but are not limited Surfactants:
Cholesterol, tweens and spans, polysorbate 80, and pluronics.

[0169] The bioadhesive polymers may be mixed with suitable excipients,
including but not limited to quickly dissolving water absorbent
sugars/starches, such as mannitol, dextrose, lactose, maltodextrins. It
is believed that because the tissues to which the solid drug delivery
system will adhere possesses a certain amount of moisture, these
sugars/starches will help absorb the moisture more quickly so that
initial bioadhesion and contact is achieved more readily.

Shape Memory Solid Drug Delivery Systems

[0170] The solid drug delivery systems described herein may comprise a
solid drug delivery system with shape-memory properties (a "shape memory
solid drug delivery system"). A shape memory solid drug delivery system,
as used herein, indicates a solid drug delivery system comprised of, e.g.
a shape memory polymer, whose macroscopic shape may be processed or
formed into a first shape, subsequently processed or formed into a second
shape, and which upon exposure to a predetermined condition changes or
reverts to a shape that is similar or identical to the first shape. The
shape memory solid drug delivery system may be made of various polymers.
For further information on shape-memory polymers, see Alteheld et al.,
Biodegradable, Amorphous Copolyester-Urethane Networks Having
Shape-Memory Properties, Andew. Chem. Int. Ed. 44: 1188-1192 (2005),
which is incorporated herein by reference in its entirety.

[0171] In some variations, a shape memory solid drug delivery system
changes or reverts to a shape that is similar or identical to the first
shape within 24, 20, 15, 10, 6, 4, 2, or 1 hours. In some variations, the
shape memory solid drug delivery system changes or reverts to a shape
that is similar or identical to the first shape within 45, 30, 20, or 10
minutes.

[0172] In some variations, a shape memory solid drug delivery system
comprises a shape memory polymer wherein the second shape of the shape
memory solid drug delivery system is smaller, more compact, or compressed
relative to the first shape. In such a variation, the shape memory solid
drug delivery system may be made smaller, more compact or compressed
relative to the first shape in order to place the solid drug delivery
system, including but not limited to via injection.

[0173] In some variations, the second shape of the shape memory solid drug
delivery system has an overall more linear shape relative to the first
shape. In such a variation, the shape memory solid drug delivery system
may be made overall more linear relative to the first shape in order to
place the solid drug delivery system, including but not limited to via
injection.

[0174] In some variations, the shape memory solid drug delivery system,
after placement in or proximal to the eye of a subject, changes or
reverts to a shape that is similar or identical to the first shape.

[0175] In some variations, the shape memory solid drug delivery system is
transparent or essentially transparent. In some variations the shape
memory solid drug delivery system is bioerodible. In some variations the
shape memory solid drug delivery system is nonbioerodible. In some
variations, the shape memory solid drug delivery system is amorphous. In
some variations the shape memory solid drug delivery system is prepared
from star-shaped hydroxyl-telechelic co-oligoesters.

Extended Delivery of Therapeutic Agents Including Rapamycin

[0176] For treatment, prevention, inhibition, delaying the onset of, or
causing the regression of certain diseases or conditions, it may be
desirable to maintain delivery of a therapeutically effective amount of
the therapeutic agent for an extended period of time. Depending on the
disease or condition being treated, prevented, inhibited, having onset
delayed, or being caused to regress this extended period of time may be
at least 30 days, at least 60 days, at least 90 days, at least 120 days,
at least 150 days, at least 180 days, at least 210 days, at least 240
days, at least 270 days, at least 300 days, at least 330 days, or at
least 360 days. Generally, however, any extended period of delivery may
be possible. A therapeutically effective amount of agent may be delivered
for an extended period by a solid drug delivery system that maintains for
the extended period a concentration of agent in a subject or an eye of a
subject sufficient to deliver a therapeutically effective amount of agent
for the extended time.

[0177] Delivery of a therapeutically effective amount of the therapeutic
agent for an extended period may be achieved using application of one
solid drug delivery system or may be achieved by application of two or
more solid drug delivery systems, either at the same time or some period
of time from one another. As a non-limiting example of such multiple
applications, maintenance of the therapeutic amount of rapamycin for 3
months for treatment of wet AMD may be achieved by application of one
solid drug delivery system delivering a therapeutic amount for 3 months
or by sequential application of a plurality of solid drug delivery
systems. The optimal dosage regime will depend on the therapeutic amount
of the therapeutic agent needing to be delivered, the period over which
it need be delivered, and the size of the system needed to satisfy these
requirements. Those versed in such extended therapeutic agent delivery
dosing will understand how to identify dosing regimes that may be used
given the teachings provided herein.

[0178] Described herein are solid drug delivery systems showing in vivo
delivery or clearance profiles with one or more of the following
characteristics. The delivery or clearance profiles are for clearance of
the therapeutic agent in vivo after placement of the solid drug delivery
system in the area between the sclera and conjunctiva of a rabbit eye.
The therapeutic agent may be any of the therapeutic agents as herein,
including but not limited to rapamycin. The solid drug delivery system
may be any solid drug delivery system described herein, including but not
limited to the solid drug delivery system prepared in Example 1. The
volume of a vitreous of a rabbit eye is approximately 30-40% of the
volume of a vitreous of a human eye. The amount of therapeutic agent is
measured using techniques as described in Example 2, but without
limitation to the solid drug delivery system and therapeutic agent
described in Example 2.

[0179] In some variations, the solid drug delivery systems described
herein may have in vivo delivery to the vitreous profiles with the
following described characteristics, where the delivery profiles are for
delivery of therapeutic agent in vivo after placement of the solid drug
delivery system into the area between the sclera and the conjunctiva of a
rabbit eye.

[0180] "Average percentage in vivo" level or concentration means that an
average concentration of therapeutic agent is obtained across multiple
rabbit eyes for a given timepoint, and the average concentration of
therapeutic agent at one timepoint is divided by the average
concentration of therapeutic agent at another timepoint. In some
variations of the average percentage in vivo levels, the therapeutic
agent is rapamycin.

[0181] In some variations at day 14 after placement, the percentage in
vivo vitreal level is between 25% and 65%, and more usually between 35%
and 55%, relative to the level present at day 1 after placement. In some
variations at day 14 after placement, the percentage in vivo vitreal
level is greater than 25%, and more usually greater than 35%, relative to
the level present at day 1 after placement.

[0182] In some variations at day 28 after placement, the percentage in
vivo vitreal level is between 55% and 95%, and more usually between 85%
and 85%, relative to the level present at day 1 after placement. In some
variations at day 28 after placement, the percentage in vivo vitreal
level is greater than 55%, and more usually greater than 65%, relative to
the level present at day 1 after placement.

[0183] In some variations at day 75 after placement, the percentage in
vivo vitreal level is between 5% and 30%, and more usually between 10%
and 25%, relative to the level present at day 1 after placement. In some
variations at day 75 after placement, the percentage in vivo vitreal
level is greater than 5%, and more usually greater than 10%, relative to
the level present at day 1 after placement.

[0184] In some variations at day 95 after placement, the percentage in
vivo vitreal level is between 90% and 150%, and more usually between 100%
and 130%, relative to the level present at day 1 after placement. In some
variations at day 95 after placement, the percentage in vivo vitreal
level is greater than 90%, and more usually greater than 100%, relative
to the level present at day 1 after placement.

[0185] In some variations, the solid drug delivery systems described
herein may have in vivo delivery to the retina choroid profiles with the
following described characteristics, where the delivery profiles are for
delivery of therapeutic agent in vivo after placement of the solid drug
delivery system into the area between the sclera and the conjunctiva of a
rabbit eye.

[0186] In some variations at day 14 after placement, the percentage in
vivo retina choroid level is between 2% and 20%, and more usually between
5% and 10%, relative to the level present at day 1 after placement. In
some variations at day 14 after placement, the percentage in vivo retina
choroid level is greater than 2%, and more usually greater than 5%,
relative to the level present at day 1 after placement.

[0187] In some variations at day 28 after placement, the percentage in
vivo retina choroid level is between 5% and 45%, and more usually between
15% and 35%, relative to the level present at day 1 after placement. In
some variations at day 28 after placement, the percentage in vivo retina
choroid level is greater than 5%, and more usually greater than 15%,
relative to the level present at day 1 after placement.

[0188] In some variations at day 75 after placement, the percentage in
vivo retina choroid level is between 2% and 35%, and more usually between
10% and 20%, relative to the level present at day 1 after placement. In
some variations at day 75 after placement, the percentage in vivo retina
choroid level is greater than 2%, and more usually greater than 10%,
relative to the level present at day 1 after placement.

[0189] In some variations at day 95 after placement, the percentage in
vivo retina choroid level is between 1% and 15%, and more usually between
4% and 10%, relative to the level present at day 1 after placement. In
some variations at day 95 after placement, the percentage in vivo vitreal
level is greater than 1%, and more usually greater than 4%, relative to
the level present at day 1 after placement.

[0190] In some variations, the solid drug delivery systems described
herein may have in vivo clearance from the sclera profiles with the
following described characteristics, where the clearance profiles are for
delivery of therapeutic agent in vivo after placement of the solid drug
delivery system into the area between the sclera and the conjunctiva of a
rabbit eye.

[0191] In some variations at day 14 after placement, the percentage in
vivo vitreal level is between 15% and 55%, and more usually between 25%
and 45%, relative to the level present at day 1 after placement. In some
variations at day 14 after placement, the percentage in vivo vitreal
level is greater than 15%, and more usually greater than 55%, relative to
the level present at day 1 after placement.

[0192] In some variations at day 28 after placement, the percentage in
vivo vitreal level is between 75% and 115%, and more usually between 85%
and 105%, relative to the level present at day 1 after placement. In some
variations at day 28 after placement, the percentage in vivo vitreal
level is greater than 75%, and more usually greater than 85%, relative to
the level present at day 1 after placement.

[0193] In some variations at day 75 after placement, the percentage in
vivo vitreal level is between 2% and 30%, and more usually between 5% and
15%, relative to the level present at day 1 after placement. In some
variations at day 75 after placement, the percentage in vivo vitreal
level is greater than 2%, and more usually greater than 5%, relative to
the level present at day 1 after placement.

[0194] In some variations at day 95 after placement, the percentage in
vivo vitreal level is between 0.5% and 10%, and more usually between 2%
and 8%, relative to the level present at day 1 after placement. In some
variations at day 95 after placement, the percentage in vivo vitreal
level is greater than 0.5%, and more usually greater than 2%, relative to
the level present at day 1 after placement.

[0195] The "average concentration" of a therapeutic agent is calculated by
(1) performing an experiment including but not limited to placing a solid
drug delivery system into the vitreous of a rabbit eye, (2) measuring the
levels of the therapeutic agent in the rabbit eye using LCMS (liquid
chromatography mass spectroscopy), and (3) taking the average of the
levels obtained in the rabbit eyes. The average may be taken on any
number higher than one. In some variations, the average is taken by
adding the levels of therapeutic agent in 2 eyes of each of two rabbits
and dividing by 4, where the solid drug delivery system was placed in
each eye analyzed.

[0196] Described herein are solid drug delivery systems showing in vivo
delivery or clearance profiles with one or more of the following
characteristics. The delivery or clearance profiles are for clearance of
the therapeutic agent in vivo after placement of the solid drug delivery
system subconjunctivally in a rabbit eye. In some variations, the
delivery or clearance profiles are for clearance of rapamycin in vivo
after placement of the solid drug delivery system subconjunctivally or
into the vitreous of a rabbit eye. The volume of the rabbit vitreous is
approximately 30-40% of the volume of the human vitreous. The amount of
therapeutic agent is measured using techniques as described in Example 2,
but without limitation to the formulation and therapeutic agent described
in Example 2.

[0197] In some variations, the therapeutic agents with the in vivo
delivery or clearance profiles described herein include but are not
limited to those described in the Therapeutic Agents section. In some
variations the therapeutic agent is rapamycin. In some variations, the
solid drug delivery systems described herein are used to deliver
therapeutic agents in a concentration equivalent to rapamycin. The solid
drug delivery systems described herein may comprise any therapeutic agent
including but not limited to those in the Therapeutic Agents section, in
a concentration equivalent to rapamycin, including but not limited to
those concentrations described herein including in the examples.

[0198] The average concentration of a therapeutic agent over a period of
time means for representative timepoints over the period of time the
average concentration at each time point. For example, if the time period
is 30 days, the average concentration may be measured at 5 day intervals:
for the average concentration at day 5, the average of a number of
measurements of concentration at day 5 would be calculated; for the
average concentration at day 10, the average of a number of measurements
of the concentration at day 10 would be calculated, etc.

[0199] In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers therapeutic
agent maintaining an average concentration of therapeutic agent in the
vitreous of the rabbit eye of at least 0.01 pg/mL for at least 30, at
least 60, at least 90, or at least 105 days after placement of the solid
drug delivery system in the rabbit eye. In some variations, the solid
drug delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent maintaining an average
concentration of therapeutic agent in the vitreous of the rabbit eye of
at least 0.001 ng/mL for at least 30, at least 60, at least 90, or at
least 105 days after placement of the solid drug delivery system in the
rabbit eyes. In some variations, the solid drug delivery system when
placed between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent maintaining an average concentration of therapeutic
agent in the vitreous of the rabbit eye of at least 0.01 ng/mL for at
least 30, at least 60, at least 90, or at least 105 days after placement
of the solid drug delivery system in the rabbit eyes. In some variations,
the solid drug delivery system when placed between the sclera and
conjunctiva of a rabbit eye delivers therapeutic agent maintaining an
average concentration of therapeutic agent in the vitreous of the rabbit
eye of at least 0.1 ng/mL for at least 30, at least 60, at least 90, or
at least 105 days after placement of the solid drug delivery system in
the rabbit eyes. In some variations, the solid drug delivery system when
placed between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent maintaining an average concentration of therapeutic
agent in the vitreous of the rabbit eye of at least 1 ng/mL for at least
30, at least 60, or at least 90 days after placement of the solid drug
delivery system in the rabbit eyes. In some variations, the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent maintaining an average
concentration of therapeutic agent in the vitreous of the rabbit eye of
at least 2.5 ng/mL for at least 30, at least 60, or at least 90 days
after placement of the solid drug delivery system in the rabbit eyes.

[0200] In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers therapeutic
agent maintaining an average concentration of therapeutic agent in the
retina choroid of the rabbit eye of at least 0.01 pg/mg for at least 30,
at least 60, at least 90, or at least 105 days after placement of the
solid drug delivery system in the rabbit eye. In some variations, the
solid drug delivery system when placed between the sclera and conjunctiva
of a rabbit eye delivers therapeutic agent maintaining an average
concentration of therapeutic agent in the retina choroid of the rabbit
eye of at least 0.1 pg/mg for at least 30, at least 60, at least 60, at
least 90, or at least 105 days after placement of the solid drug delivery
system in the rabbit eyes. In some variations, the solid drug delivery
system when placed between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent maintaining an average concentration of
therapeutic agent in the retina choroid of the rabbit eye of at least 1
pg/mg for at least 30, at least 60, at least 90, or at least 105 days
after placement of the solid drug delivery system in the rabbit eyes. In
some variations, the solid drug delivery system when placed between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent
maintaining an average concentration of therapeutic agent in the retina
choroid of the rabbit eye of at least 0.01 ng/mg for at least 30, at
least 60, at least 90, or at least 105 days after placement of the solid
drug delivery system in the rabbit eyes. In some variations, the solid
drug delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent maintaining an average
concentration of therapeutic agent in the retina choroid of the rabbit
eye of at least 0.1 ng/mg for at least 30, at least 60, or at least 90
days after placement of the solid drug delivery system in the rabbit
eyes.

[0201] In some variations, a solid drug delivery system described herein
delivers a level of a therapeutic agent to the specified tissue that is
approximately constant over a period of time. "Approximately constant,"
as used herein, means that the average level does not vary by more than
one order of magnitude over the extended period of time, i.e., the
difference between the maximum and minimum is less than a 10-fold
difference for measurements of the average concentration at times in the
relevant period of time. In some variations, the therapeutic agent is
rapamycin and the level of rapamycin is approximately constant over the
specified period of time in the specified tissue.

[0202] In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the
vitreous of a rabbit eye that is approximately constant at a value
greater than 0.001 ng/mL between day 14 to at least day 28, at least day
75, at least day 95, or at least day 107 after placement of the solid
drug delivery system in the rabbit eye. In some variations, the solid
drug delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of a rabbit eye that is approximately
constant at a value greater than 0.01 ng/mL between day 14 to at least
day 28, at least day 75, at least day 95, or at least day 107 after
placement of the solid drug delivery system in the rabbit eye. In some
variations, the solid drug delivery system when placed between the sclera
and conjunctiva of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the vitreous of a rabbit
eye that is approximately constant at a value greater than 0.1 ng/mL
between day 14 to at least day 28, at least day 75, at least day 95, or
at least day 107 after placement of the solid drug delivery system in the
rabbit eye. In some variations, the solid drug delivery system when
placed between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic agent in
the vitreous of a rabbit eye that is approximately constant at a value of
0.75 ng/mL between day 14 to at least day 28, at least day 75, at least
day 95, or at least day 107 after placement of the solid drug delivery
system in the rabbit eye. In some variations, the solid drug delivery
system when placed between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of therapeutic
agent in the vitreous of a rabbit eye that is approximately constant at a
value of 1 ng/mL between day 14 to at least day 28, at least day 75, at
least day 95, or at least day 107 after placement of the solid drug
delivery system in the rabbit eye.

[0203] In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the retina
choroid of the rabbit eye of at least 0.001 ng/mg between day 14 to at
least day 28, at least day 75, at least day 95, or at least day 107 after
placement of the solid drug delivery system in the rabbit eye. In some
variations, the solid drug delivery system when placed between the sclera
and conjunctiva of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid of the
rabbit eye of at least 0.005 ng/mg between day 14 to at least day 28, at
least day 75, at least day 95, or at least day 107 after placement of the
solid drug delivery system in the rabbit eye. In some variations, the
solid drug delivery system when placed between the sclera and conjunctiva
of a rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the retina choroid of the rabbit
eye of at least 0.01 between day 14 to at least day 28, at least day 75,
at least day 95, or at least day 107 after placement of the solid drug
delivery system in the rabbit eye. In some variations, the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent giving an average concentration of
therapeutic agent in the retina choroid of the rabbit eye of at least
0.03 between day 14 to at least day 28, at least day 75, at least day 95,
or at least day 107 after placement of the solid drug delivery system in
the rabbit eye.

[0204] In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the sclera
of the rabbit eye of at least 0.001 ng/mg between day 42 to at least day
63, or at least day 91 after placement of the solid drug delivery system
in the rabbit eye. In some variations, the solid drug delivery system
when placed between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic agent in
the sclera of the rabbit eye of at least 0.005 ng/mg between day 42 to at
least day 63, or at least day 91 after placement of the solid drug
delivery system in the rabbit eye. In some variations, the solid drug
delivery system when placed between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent giving an average concentration of
therapeutic agent in the sclera of the rabbit eye of at least 0.01 ng/mg
between day 42 to at least day 63, or at least day 91 after placement of
the solid drug delivery system in the rabbit eye. In some variations, the
solid drug delivery system when placed between the sclera and conjunctiva
of a rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the sclera of the rabbit eye of at
least 0.03 ng/mg between day 42 to at least day 63, or at least day 91
after placement of the solid drug delivery system in the rabbit eye. In
some variations, the solid drug delivery system when placed between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the sclera of the rabbit
eye of at least 0.1 ng/mg between day 42 to at least day 63, or at least
day 91 after placement of the solid drug delivery system in the rabbit
eye. In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the sclera
of the rabbit eye of at least 1.0 ng/mg between day 42 to at least day
63, or at least day 91 after placement of the solid drug delivery system
in the rabbit eye.

[0205] In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers a therapeutic
agent to give an average concentration of the therapeutic agent in the
vitreous of the rabbit eye of between 0.001 and 15.0 ng/ml for at least
14, at least 28, at least 75, at least 95, or at least 107 days after
administration of the solid drug delivery system to the rabbit eye. In
some variations, the solid drug delivery system when placed between the
sclera and conjunctiva of a rabbit eye delivers a therapeutic agent to
give an average concentration of the therapeutic agent in the vitreous of
the rabbit eye of between 0.01 and 10.0 ng/ml for at least 14, at least
28, at least 75, at least 95, or at least 107 days after administration
of the solid drug delivery system to the rabbit eye. In some variations,
the solid drug delivery system when placed between the sclera and
conjunctiva of a rabbit eye delivers a therapeutic agent to give an
average concentration of the therapeutic agent in the vitreous of the
rabbit eye of between 0.1 and 10.0 ng/ml for at least 14, at least 28, at
least 75, at least 95, or at least 107 days after administration of the
solid drug delivery system to the rabbit eye.

[0206] In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers a therapeutic
agent to give an average concentration of the therapeutic agent in the
retina choroid of the rabbit eye of between 0.001 and 5.0 ng/mg for at
least 14, at least 28, at least 75, at least 95, or at least 107 days
after administration of the solid drug delivery system to the rabbit eye.
In some variations, the solid drug delivery system when placed between
the sclera and conjunctiva of a rabbit eye delivers a therapeutic agent
to give an average concentration of the therapeutic agent in the retina
choroid of the rabbit eye of between 0.001 and 1.25 ng/mg for at least
14, at least 28, at least 75, at least 95, or at least 107 days after
administration of the solid drug delivery system to the rabbit eye. In
some variations, the solid drug delivery system when placed between the
sclera and conjunctiva of a rabbit eye delivers a therapeutic agent to
give an average concentration of the therapeutic agent in the retina
choroid of the rabbit eye of between 0.01 and 5.0 ng/mg for at least 14,
at least 28, at least 75, at least 95, or at least 107 days after
administration of the solid drug delivery system to the rabbit eye.

[0207] In some variations, the solid drug delivery system when placed
between the sclera and conjunctiva of a rabbit eye delivers a therapeutic
agent to give an average concentration of the therapeutic agent in the
sclera of the rabbit eye of between 0.001 and 10.0 ng/mg for at least 14,
at least 28, at least 75, at least 95, or at least 107 days after
administration of the solid drug delivery system to the rabbit eye. In
some variations, the solid drug delivery system when placed between the
sclera and conjunctiva of a rabbit eye delivers a therapeutic agent to
give an average concentration of the therapeutic agent in the sclera of
the rabbit eye of between 0.01 and 10.0 ng/mg for at least 14, at least
28, at least 75, at least 95, or at least 107 days after administration
of the solid drug delivery system to the rabbit eye. In some variations,
the solid drug delivery system when placed between the sclera and
conjunctiva of a rabbit eye delivers a therapeutic agent to give an
average concentration of the therapeutic agent in the sclera of the
rabbit eye of between 0.1 and 200.0 ng/mg for at least 14, at least 42,
at least 63, or at least 91 days after administration of the solid drug
delivery system to the rabbit eye.

Therapeutic Agents

[0208] Most generally, any compounds and compositions currently known or
yet to be discovered that are useful in treating, preventing, inhibiting,
delaying the onset of, or causing the regression of the diseases and
conditions described herein may be therapeutic agents for use in the
solid drug delivery systems and methods described herein.

[0209] Therapeutic agents that may be used include compounds that act by
binding members of the immunophilin family of cellular proteins. Such
compounds are known as "immunophilin binding compounds." Immunophilin
binding compounds include but are not limited to the "limus" family of
compounds. Examples of compounds that may be used include but are not
limited to cyclophilins, sirolimus (rapamycin) and its water soluble
analog SDZ-RAD (Novartis), TAFA-93 (Isotechnika), tacrolimus, everolimus,
RAD-001 (Novartis), pimecrolimus, temsirolimus, CCI-779 (Wyeth), AP23841
(Ariad), AP23573 (Ariad), and ABT-578 (Abbott Laboratories). Limus
compound analogs and derivatives that may be used include but are not
limited to the compounds described in U.S. Pat. Nos. 5,527,907;
6,376,517; and 6,329,386 and U.S. patent application Ser. No. 09/950,307,
each of which is incorporated herein by reference in their entirety.
Therapeutic agents also include analogs, prodrugs, salts and esters of
limus compounds.

[0210] The terms rapamycin, rapa, and sirolimus are used interchangeably
herein.

[0212] The limus family of compounds may be used in the solid drug
delivery systems and methods for the treatment, prevention, inhibition,
delaying the onset of, or causing the regression of angiogenesis-mediated
diseases and conditions of the eye, including choroidal
neovascularization. The limus family of compounds may be used to prevent,
treat, inhibit, delay the onset of, or cause regression of AMD, including
wet AMD. Rapamycin and rapamycin derivatives and analogs may be used to
prevent, treat, inhibit, delay the onset of, or cause regression of
angiogenesis-mediated diseases and conditions of the eye, including
choroidal neovascularization. Rapamycin may be used to prevent, treat,
inhibit, delay the onset of, or cause regression of AMD, including wet
AMD. In some variations, a member of the limus family of compounds or
rapamycin is used to treat wet AMD or angiogenesis-mediated diseases and
conditions of the eye including choroidal neovascularization.

[0213] Other therapeutic agents that may be used include those disclosed
in the following patents and publications, the contents of each of which
is incorporated herein by reference in its entirety: PCT publication WO
2004/027027, published Apr. 1, 2004, titled Method of inhibiting
choroidal neovascularization, assigned to Trustees of the University of
Pennsylvania; U.S. Pat. No. 5,387,589, issued Feb. 7, 1995, titled Method
of Treating Ocular Inflammation, with inventor Prassad Kulkarni, assigned
to University of Louisville Research Foundation; U.S. Pat. No. 6,376,517,
issued Apr. 23, 2003, titled Pipecolic acid derivatives for vision and
memory disorders, assigned to GPI NIL Holdings, Inc; PCT publication WO
2004/028477, published Apr. 8, 2004, titled Method subretinal
administration of therapeutics including steroids: method for localizing
pharmadynamic action at the choroid and retina; and related methods for
treatment and or prevention of retinal diseases, assigned to Innorx, Inc;
U.S. Pat. No. 6,416,777, issued Jul. 9, 2002, titled Ophthalmic drug
delivery device, assigned to Alcon Universal Ltd; U.S. Pat. No.
6,713,081, issued Mar. 30, 2004, titled Ocular therapeutic agent delivery
device and methods for making and using such devices, assigned to
Department of Health and Human Services; U.S. Pat. No. 5,100,899, issued
Mar. 31, 1992, titled Methods of inhibiting transplant rejection in
mammals using rapamycin and derivatives and prodrugs thereof.

[0217] In some variations, cortisone, dexamethasone, fluocinolone,
hydrocortisone, methylprednisolone, prednisolone, prednisone, and
triamcinolone, or their derivatives, may be used. The solid drug delivery
system may include a combination of two or more steroidal therapeutic
agents.

[0218] In one nonlimiting example, the steroidal therapeutic agents may
constitute from 0.05% to 50% by weight of the solid drug delivery system.
In another nonlimiting example, the steroid constitutes from 0.05% to
10%, between 10% to 20%; between 30% to 40%; or between 40% to 50% by
weight of the solid drug delivery system.

Diseases and Conditions that May be Treated, Prevented, Inhibited, Onset
Delayed, or Regression Caused

[0223] Herein are described diseases and conditions that may be treated,
prevented, inhibited, onset delayed, or regression caused using the
therapeutic agents, solid drug delivery systems and methods described
herein. In some variations, the diseases or conditions are treated using
one or more of a solid drug delivery system comprising a therapeutic
agent or a method described herein. Unless the context indicates
otherwise, it is envisioned that the subjects on whom all of the methods
of treatment may be performed include, but are not limited to, human
subjects.

[0224] Generally, any disease or condition of the eye susceptible to
treatment, prevention, inhibition, delaying the onset of, or causing the
regression of using the therapeutic agents and the solid drug delivery
systems and methods described herein may be treated, prevented,
inhibited, onset delayed, or regression caused treated or prevented.
Examples of diseases or conditions of the eye include, but are not
limited to, diseases or conditions associated with neovascularization
including retinal and/or choroidal neovascularization.

[0226] When used to treat, prevent, inhibit, delay the onset of, or cause
regression of uveitis, the solid drug delivery systems described herein
may be placed in the subject by a variety or routes as is known in the
art, including but not limited to by ocular or oral administration. Other
methods of placement are known and are routine in the art. Some examples
thereof are listed in the herein.

[0227] One disease that may be treated, prevented inhibited, have onset
delayed, or be caused to regress using the solid drug delivery systems
and methods described herein is the wet form of AMD. The wet form of AMD
is characterized by blood vessels growing from their normal location in
the choroid into an undesirable position under the retina. Leakage and
bleeding from these new blood vessels results in vision loss and possibly
blindness.

[0228] The dry form of AMD is associated with the retinal pigment
epithelium or RPE degenerating and leading to photoreceptor cell death,
and the formation of yellow deposits called drusen under the retina. The
solid drug delivery systems and methods described herein may also be used
to prevent or slow the transition from the dry form of AMD to the wet
form of AMD.

[0229] "Macular degeneration" is characterized by the excessive buildup of
fibrous deposits in the macula and retina and the atrophy of the retinal
pigment epithelium. As used herein, an eye "afflicted" with macular
degeneration is understood to mean that the eye exhibits at least one
detectable physical characteristic associated with the disease of macular
degeneration. The administration of rapamycin appears to limit excessive
angiogenesis, such as choroidal neovascularization in age-related macular
degeneration (AMD), which may occur without such treatment. As used
herein, the term "angiogenesis" means the generation of new blood vessels
("neovascularization") into a tissue or organ. An "angiogenesis-mediated
disease or condition" of the eye or retina is one in which new blood
vessels are generated in a pathogenic manner in the eye or retina,
resulting in loss of vision or other problem, e.g., choroidal
neovascularization associated with AMD.

[0230] The solid drug delivery systems described herein, including but not
limited to rapamycin-containing solid drug delivery systems, may also be
used to treat, prevent, inhibit, delay the onset of, or cause regression
of various immune-related diseases and conditions, including but not
limited to organ transplant rejection in a host, graft vs. host disease,
autoimmune diseases, diseases of inflammation, hyperproliferative
vascular disorders, solid tumors, and fungal infections. The solid drug
delivery systems described herein, including but not limited to
rapamycin-containing solid drug delivery systems, may be used as
immunosuppressants. The solid drug delivery systems described herein,
including but not limited to rapamycin-containing solid drug delivery
systems, may be used to treat, prevent, inhibit, or delay the onset of
rejection of transplanted organs or tissues including but not limited to
transplanted heart, liver, kidney, spleen, lung, small bowel, pancreas,
and bone marrow. When used to treat, prevent, inhibit, delay the onset
of, or cause regression of immune-related diseases, including but not
limited to transplant rejection, the solid drug delivery systems
described herein may be placed in the subject by a variety or routes as
is known in the art, including but not limited to by oral administration.

[0231] In some variations, the solid drug delivery systems described
herein are used to prevent or delay onset of a disease or condition of
the eye where the subject, including but not limited to a human subject,
is at heightened risk of developing the disease or condition of the eye.
A subject with a heightened risk of developing a disease or condition is
a subject with one or more indications that the disease or condition is
likely to develop in the particular subject.

[0232] In some variations the subject with a heightened risk of developing
wet AMD is a subject with dry AMD in at least one eye. In some variations
the subject with a heightened risk of developing wet AMD in a fellow eye
is a subject with wet AMD in the other eye. In some variations, the solid
drug delivery systems described herein are used to prevent or delay onset
of CNV in a subject at heightened risk of developing CNV, including but
not limited to prevention or delaying onset of CNV in the fellow eye of a
subject, including but not limited to a human subject with AMD in one
eye. In some variations, the solid drug delivery systems described herein
are used to prevent or delay onset of CNV in the fellow eye of a subject
with wet AMD in one eye.

[0233] In some variations, the solid drug delivery systems comprise a
limus compound, including but not limited to rapamycin.

[0234] In some variations the solid drug delivery systems are administered
periocularly, including without limitation subconjunctivally, to a human
subject with vision of 20/40 or better. In some variations, the solid
drug delivery systems are administered periocularly, including without
limitation subconjunctivally or transsclerally, to the eye of a human
subject where the eye to which the formulation is administered has vision
of 20/40 or better.

[0235] In some variations, the solid drug delivery systems described
herein are used to treat, prevent, or delay onset of AMD. In some
variations, the solid drug delivery systems described herein are used to
treat, prevent, or delay onset of dry AMD. In some variations, subjects
including but not limited to human subjects with non-central geographic
atrophy are administered a solid drug delivery system described herein to
treat, prevent, or delay onset of central geographic atrophy. In some
variations, the solid drug delivery systems comprise a limus compound,
including but not limited to rapamycin. In some variations the solid drug
delivery systems are administered periocularly, including without
limitation subconjunctivally or transsclerally, to a human subject with
vision of 20/40 or better. In some variations, the solid drug delivery
systems described herein are administered and the subject, including but
not limited to a human subject is also treated with a second therapy for
treating the disease or disorder. In some variations, the solid drug
delivery systems described herein are used to treat, prevent, or delay
onset of wet or dry AMD and the subject, including but not limited to a
human subject is also treated with laser therapy such as photodynamic
laser therapy, either before, during, or after treatment with the
formulations or pharmaceutical formulations described herein.

[0236] In some variations, the solid drug delivery systems described
herein are used to treat one or more of uveitis, allergic conjunctivitis,
macular edema, glaucoma, or dry eye.

[0237] In some variations, a solid drug delivery system comprises a limus
compound such as rapamycin, and is administered to treat, prevent, or
delay onset of dry eye. In some variations, a solid drug delivery system
comprises a limus compound such as rapamycin, and is administered to
treat, prevent, or delay onset of allergic conjunctivitis.

[0238] In some variations, the methods or solid drug delivery systems
described herein are used to treat retinitis pigmentosa. In some
variations, the solid drug delivery systems described herein comprise a
limus compound such as rapamycin, and are used to treat, prevent, or
delay onset of retinitis pigmentosa. In some variations, the solid drug
delivery systems described herein have a neuroprotective effect and are
used to treat retinitis pigmentosa.

[0239] In some variations, the solid drug delivery systems described
herein are used to treat one or more of central retinal vein occlusive
diseases (CRVO), branch retinal venous occlusion (BRVO), retinal vascular
diseases and conditions, macular edema, diabetic macular edema, iris
neovascularization, diabetic retinopathy, or corneal graft rejection. In
some variations, a solid drug delivery system comprises a limus compound
such as rapamycin, and is administered to treat, prevent, or delay onset
of one or more of these diseases or conditions. In some variations the
solid drug delivery systems are administered subconjunctivally to an eye
with vision of 20/40 or better.

[0240] Routes of administration are described elsewhere herein.

[0241] Other diseases and conditions that may be treated, prevented,
inhibited, have the onset delayed, or be caused to regress using the
methods described herein include those disclosed in the following patents
and publications, the contents of each of which is incorporated herein in
its entirety: PCT publication WO 2004/027027, published Apr. 1, 2004,
titled Method of inhibiting choroidal neovascularization, assigned to
Trustees of the University of Pennsylvania; U.S. Pat. No. 5,387,589,
issued Feb. 7, 1995, titled Method of Treating Ocular Inflammation, with
inventor Prassad Kulkami, assigned to University of Louisville Research
Foundation; U.S. Pat. No. 6,376,517, issued Apr. 23, 2003, titled
Pipecolic acid derivatives for vision and memory disorders, assigned to
GPI NIL Holdings, Inc; PCT publication WO 2004/028477, published Apr. 8,
2004, titled Method subretinal administration of therapeutics including
steroids: method for localizing pharmadynamic action at the choroid and
retina; and related methods for treatment and or prevention of retinal
diseases, assigned to Innorx, Inc; U.S. Pat. No. 6,416,777, issued Jul.
9, 2002, titled Ophthalmic drug delivery device, assigned to Alcon
Universal Ltd; U.S. Pat. No. 6,713,081, issued Mar. 30, 2004, titled
Ocular therapeutic agent delivery device and methods for making and using
such devices, assigned to Department of Health and Human Services; and
U.S. Pat. No. 5,536,729, issued Jul. 16, 1996, titled Rapamycin
Formulations for Oral Administration, assigned to American Home Products
Corp., and U.S. Pat. App. No. 60/503,840 and Ser. No. 10/945,682.

[0242] When a certain amount of a solid drug delivery system is
administered, it is understood that there is some imprecision in the
accuracy of various devices that may be used to administer the solid drug
delivery system. Where a certain amount is specified, it is understood
that this is the target amount.

[0243] When the therapeutic agent is rapamycin, the solid drug delivery
system may be used to maintain an amount of rapamycin in the vitreous
effective to treat wet AMD. In one nonlimiting example, it is believed
that a solid drug delivery system delivering rapamycin to maintain a
concentration of rapamycin of 10 pg/ml to 2 .mu.g/ml in the vitreous over
a period of time may be used for the treatment of wet AMD. In another
nonlimiting example, it is believed that a delivery system delivering
rapamycin to maintain a concentration of rapamycin of 0.01 pg/mg to 10
ng/mg in the retina choroid over a period of time may be used for
treatment of wet AMD. Other therapeutically effective amounts of
therapeutic agent are also possible, and can be readily determined by one
of skill in the art given the teachings herein.

[0244] When the therapeutic agent is rapamycin, the solid drug delivery
systems described herein may be used to deliver a dose of rapamycin to a
subject, including but not limited to a human subject or to the eye of a
subject. In one nonlimiting example, it is believed that a solid drug
delivery system containing a dose of 20 .mu.g to 4 mg may be used for the
treatment of wet AMD.

[0245] The amount of therapeutic agent component delivered may also be
represented as a concentration equivalent to rapamycin. As used herein,
"a concentration equivalent to rapamycin" refers to a concentration of a
therapeutic agent that will have approximately the same efficacy in vivo
as a particular dose of rapamycin for treating, preventing, delaying, or
inhibiting a disease or condition, including but not limited to the
diseases and conditions described herein. As a nonlimiting example, if a
therapeutic agent is found to be approximately 25-fold less potent or
efficacious than rapamycin in the treatment of wet AMD, a concentration
of 25 ng/ml of the therapeutic agent would be equivalent to a 1 ng/ml
concentration of rapamycin when used for the treatment of wet AMD.

[0246] Those of skill in the art, based on the teachings herein can
determine what amount or concentration of a given therapeutic agent is
equivalent to an amount or concentration of rapamycin by, for example,
administering the therapeutic agent at various amounts or concentrations
to a disease model system, such as an in vivo or in vivo model system,
and comparing the results in the model system relative to the results of
various amounts or concentrations of rapamycin. Those of skill in the
art, based on the teachings herein can also determine what amount or
concentration of a given therapeutic agent is equivalent to an amount or
concentration of rapamycin by reviewing the scientific literature for
experiments performed comparing rapamycin to other therapeutic agents. It
is understood that even the same therapeutic agent may have a different
equivalent level of rapamycin when, for example, a different disease or
disorder is being evaluated, or a different type of formulation is used.
Nonlimiting examples of scientific references with comparative studies of
rapamycin and other therapeutic agents on ocular disease are Ohia et al.,
Effects of steroids and immunosuppressive drugs on endotoxin-uveitis in
rabbits, J. Ocul. Pharmacol. 8(4):295-307 (1992); Kulkarni, Steroidal and
nonsteroidal drugs in endotoxin-induced uveitis, J. Ocul. Pharmacol.
10(1):329-34 (1994); Hafizi et al., Differential effects of rapamycin,
cyclosporine A, and FK506 on human coronary artery smooth muscle cell
proliferation and signaling, Vascul Pharmacol. 41(4-5):167-76 (2004); and
U.S. 2005/0187241.

[0247] For example, in a model for wet AMD, if a therapeutic agent is
found to be approximately 10-fold less potent or efficacious than
rapamycin in the treatment of wet AMD, a concentration of 10 ng/ml of the
therapeutic agent would be equivalent to a 1 ng/ml concentration of
rapamycin. Or if a therapeutic agent is found to be approximately 10-fold
less potent or efficacious than rapamycin in the treatment of wet AMD, a
10-fold amount of the therapeutic agent would be administered relative to
the amount of rapamycin.

Methods of Preparing Solid Drug Delivery Systems

[0248] Various methods as are known to those versed in the technology may
be used to prepare the solid drug delivery systems described herein. In
one method described herein, a solid drug delivery system may be made by
mixing the therapeutic agent with an excipient including but not limited
to a solvent, adding other excipient(s) as desired, and shaping the
resulting solid drug delivery system. In some variations, after the solid
drug delivery system was prepared the solvent was substantially absent
from the solid drug delivery system. In some variations the solvent was
evaporated using known methods of drying.

[0249] Various methods of shaping the solid drug delivery system may be
used. In some variations, the solid drug delivery system is cast as a
film on a sheet of released coated paper or polyester film, using a die
(knife-over-roll). The resultant solid drug delivery system may
subsequently be die-cut into a size and shape.

[0250] In some variations, the therapeutic agent and the excipient or
excipients are blended by thermal melting. The mix may be sent through an
extruder and a die to obtain a solid drug delivery system. The mix can
also be injection-molded to a specific shape and size wafer.

[0251] In some variations, a solid drug delivery system described herein
is made stable by a method described in U.S. 60/772,018, filed Feb. 9,
2006 with attorney docket number 57796-30010.00, titled STABLE
FORMULATIONS, AND METHODS OF THEIR PREPARATION AND USE, which is
incorporated herein by reference in its entirety for all purposes. In
some variations, a solid drug delivery system described herein is
prepared or is preparable by a method described in U.S. 60/772,018, filed
Feb. 9, 2006 with attorney docket number 57796-30010.00, titled STABLE
FORMULATIONS, AND METHODS OF THEIR PREPARATION AND USE.

Methods of Treatment

[0252] Unless the context clearly indicates otherwise, any of the
therapeutic agents described herein may be used in a method for treating,
preventing, inhibiting, delaying on set of, or causing the regression of
any of the diseases and conditions described herein.

[0253] In some variations any one or more of the solid drug delivery
systems described herein are used to deliver one or more therapeutic
agents described herein via a method described herein. Generally, the
therapeutic agent may be formulated in any solid drug delivery system
capable of delivery of a therapeutically effective amount of the
therapeutic agent to a subject or to the subject for the required
treatment period. In some variations the required treatment period is met
by a single administration of a sustained release solid drug delivery
system that is predicted to deliver an effective amout of the therapeutic
agent for the predicted duration period of the disease or condition. In
some variations the required treatment period is met by multiple
administrations of a solid drug delivery system, including but not
limited to a sustained release formulation. In some variations the
multiple administrations are at different times, at the same time in
different places, or a combination thereof.

[0254] As used herein, to "inhibit" a disease or condition by
administration of a therapeutic agent means that the progress of at least
one detectable physical characteristic or symptom of the disease or
condition is slowed or stopped following administration of the
therapeutic agent as compared to the progress of the disease or condition
without administration of the therapeutic agent.

[0255] As used herein, to "prevent" a disease or condition by
administration of a therapeutic agent means that the detectable physical
characteristics or symptom of the disease or condition do not develop
following administration of the therapeutic agent.

[0256] As used herein, to "delay onset of" a disease or condition by
administration of a therapeutic agent means that at least one detectable
physical characteristic or symptom of the disease or condition develops
later in time following administration of the therapeutic agent as
compared to the progress of the disease or condition without
administration of the therapeutic agent.

[0257] As used herein, to "treat" a disease or condition by administration
of a therapeutic agent means that the progress of at least one detectable
physical characteristic or symptom of the disease or condition is slowed,
stopped, or reversed following administration of the therapeutic agent as
compared to the progress of the disease or condition without
administration of the therapeutic agent.

[0258] As used herein, to "cause regression of" a disease or condition by
administration of a therapeutic agent means that the progress of at least
one detectable physical characteristic or symptom of the disease or
condition is reversed to some extent following administration of the
therapeutic agent.

[0259] A subject, including but not limited to a human subject, having a
predisposition for or in need of prevention may be identified by the
skilled practitioner by established methods and criteria in the field
given the teachings herein. The skilled practitioner may also readily
diagnose individuals as in need of inhibition or treatment based upon
established criteria in the field for identifying angiogenesis and/or
neovascularization given the teachings herein.

[0260] As used herein, a "subject" is generally any animal that may
benefit from administration of the therapeutic agents described herein.
In some variations the therapeutic agents are administered to a mammalian
subject. In some variations the therapeutic agents are administered to a
human subject. In some variations the therapeutic agents may be
administered to a veterinary animal subject. In some variations the
therapeutic agents may be administered to a model experimental animal
subject.

[0261] An "effective amount," which is also referred to herein as a
"therapeutically effective amount," of a therapeutic agent for
administration as described herein is that amount of the therapeutic
agent that provides the therapeutic effect sought when administered to
the subject, including but not limited to a human subject. The achieving
of different therapeutic effects may require different effective amounts
of therapeutic agent. For example, the therapeutically effective amount
of a therapeutic agent used for preventing a disease or condition may be
different from the therapeutically effective amount used for treating,
inhibiting, delaying the onset of, or causing the regression of the
disease or condition. In addition, the therapeutically effective amount
may depend on the age, weight, and other health conditions of the subject
as is well know to those versed in the disease or condition being
addressed. Thus, the therapeutically effective amount may not be the same
in every subject to which the therapeutic agent is administered.

[0262] An effective amount of a therapeutic agent for treating,
preventing, inhibiting, delaying the onset of, or causing the regression
of a specific disease or condition is also referred to herein as the
amount of therapeutic agent effective to treat, prevent, inhibit, delay
the onset of, or cause the regression of the disease or condition.

[0263] Nonlimiting examples of ways to determine whether a level of
therapeutic agent is a "therapeutically effective amount" to treat,
prevent, inhibit, delay on set of, or cause the regression of the
diseases and conditions described in the Diseases and Conditions section,
a solid drug delivery system may be administered in in vitro or animal
models for the diseases or conditions of interest, and the effects may be
observed. In addition, dose ranging human clinical trials may be
conducted to determine the therapeutically effective amount of a
therapeutic agent.

Routes of Administration

[0264] The solid drug delivery systems described herein may be
administered to a subject, including but not limited to a human subject,
by one or more of the routes of administration described herein.

[0265] The solid drug delivery systems described herein may be placed in a
subject or to the eye of a subject, including placement subtenon,
posterior juxtascleral, or in or proximal to the conjunctiva, in or
proximal to the area between the sclera and conjunctiva, or in or
proximal to the sclera of the human subject. The solid drug delivery
system so placed may deliver the therapeutic agent

[0266] In some variations, the solid drug delivery systems and methods
described herein deliver one or more therapeutic agents proximal to an
area where a disease or condition is to be treated, prevented, inhibited,
onset delayed, or regression caused.

[0267] In some variations, the solid drug delivery systems and methods
described herein deliver one or more therapeutic agents to an eye of a
subject, including the macula and the retina choroid, in an amount and
for a duration effective to treat, prevent, inhibit, delay the onset of,
or cause the regression of the diseases and conditions described in the
Diseases and Conditions section.

[0268] "Retina choroid" and "retina choroid tissues," as used herein, are
synonymous and refer to the combined retina and choroid tissues of the
eye.

[0269] As a non-limiting example, the solid drug delivery systems
described herein may be placed subtenon, posterior juxtascleral, or in or
proximal to the conjunctiva, in or proximal to the area between the
sclera and conjunctiva, or in or proximal to the sclera of the human
subject, either by direct administration to these tissues or by
periocular routes, in amounts and for a duration effective to treat,
prevent, inhibit, delay the onset of, or cause the regression of CNV and
wet AMD. The effective amounts and durations may be different for each of
treating, preventing, inhibiting, delaying the onset of, or causing the
regression of CNV and wet AMD, and for each of the different sites of
delivery. For a description of exemplary periocular routes for retinal
drug delivery, see Periocular routes for retinal drug delivery, Raghava
et al. (2004), Expert Opin. Drug Deliv. 1(1):99-114, which is
incorporated herein by reference in its entirety.

[0270] Routes of administration include but are not limited to placement
of the solid drug delivery system via forceps or by injection into a
medium in the body, including but not limited to intraocular and
periocular placement.

[0271] Intravitreal administration is more invasive than some other types
of ocular procedures. Because of the potential risks of adverse effects,
intravitreal administration may not be optimal for treatment of
relatively healthy eyes. By contrast, periocular administration, such as
subconjunctival administration, is much less invasive than intravitreal
administration. When a therapeutic agent is delivered by a periocular
route, it may be possible to treat patients with healthier eyes than
could be treated using intravitreal administration. In some variations,
subconjunctival placement is used to prevent or delay onset of a disease
or condition of the eye, where the eye of the subject has visual acuity
of 20/40 or better.

[0272] "Subconjunctival" placement or injection, as used herein, refers to
placement or injection between the sclera and conjunctiva.
Subconjunctival is sometimes referred to herein as "sub-conj"
administration. Subconjunctival delivery may be by placement or injection
of a solid drug delivery system comprising a therapeutic agent underneath
the conjunctiva, or in the area between the sclera and conjunctiva. Local
pressure to the subconjunctival site of therapeutic agent placement may
elevate delivery of the therapeutic agent to the posterior segment by
reducing local choroidal blood flow.

[0273] In some variations the solid drug delivery systems described herein
may be placed by injection or placement using forceps. In some variations
the solid drug delivery systems may be placed in various positions within
the ocular, periocular or other region for delivery to a subject or to
the eye of a subject. In some variations, solid drug delivery systems up
to 2 mm thick and 5 mm long are placed in or proximal to the eye of a
subject.

[0274] Placement of the solid drug delivery system comprising a
therapeutic agent into the vitreous may provide a high local
concentration of therapeutic agent in the vitreous and retina. Further,
it has been found that in the vitreous the clearance half-lives of drugs
increases with molecular weight.

[0275] Intracameral delivery, e.g. by placement or injection into the
anterior chamber of they eye, may also be used.

[0276] Subtenon placement may be by placement or injection of therapeutic
agent into the tenon's capsule around the upper portion of the eye and
into the "belly" of the superior rectus muscle.

[0277] Retrobulbar placement refers to placement, e.g. by injection, into
the conical compartment of the four rectus muscles and their
intermuscular septa, behind the globe of the eye.

[0278] Peribulbar placement may be at a location external to the confines
of the four rectus muscles and their intramuscular septa, i.e., outside
of the muscle cone.

[0279] Posterior juxtascleral placement refers to placement of a
therapeutic agent near and above the macula, in direct contact with the
outer surface of the sclera, and without puncturing the eyeball.

[0280] For a description of exemplary methods or sites for placement or
injection via periocular routes for retinal drug delivery, see Periocular
routes for retinal drug delivery, Raghava et al. (2004), Expert Opin.
Drug Deliv. 1(1):99-114, which is incorporated herein by reference in its
entirety.

[0281] In some variations the solid drug delivery system is placed in an
ocular region for transscleral delivery by a variety of means including
but not limited to placement inside a surgically formed scleral flap, and
placement proximal to the outer scleral surface. Positions in which the
solid polymer implant may be placed include but are not limited to
subconjunctival placement, subtenon placement, and intrascleral
placement.

[0282] In some variations of placement in a scleral flap, either in the
clinic, procedure room, or operating room the eye may be prepared in a
standard preoperative manner, the sclera will be exposed, and the
creation of the flap is performed with an appropriate blade. A suture may
or may not be required. In some variations of placement proximal to the
outer scleral surface, either in the clinic, procedure room, or operating
room the eye is prepared in a standard preoperative manner, the sclera is
exposed, and the solid polymer implant placed on or attached to the outer
surface of the sclera.

[0283] Routes of administration that may be used to administer a solid
drug delivery system include but are not limited to placement of the
solid drug delivery systems into the eye of a subject, including but not
limited to a human subject. The solid drug delivery systems may be
administered systemically, including but not limited to the following
delivery routes: rectal, vaginal, infusion, intramuscular,
intraperitoneal, intraarterial, intrathecal, intrabronchial,
intracisternal, cutaneous, subcutaneous, intradermal, transdermal,
intravenous, intracervical, intraabdominal, intracranial, intraocular,
intrapulmonary, intrathoracic, intratracheal, nasal, buccal, sublingual,
oral, parenteral, or nebulised or aerosolized using aerosol propellants.

[0284] Solid drug delivery systems comprising one or more therapeutic
agents can be administered directly to the eye using a variety of
procedures, including but not limited to procedures in which (1) the
solid drug delivery system is administered by injection using a syringe
and hypodermic needle, (2) a specially designed device is used to place
the solid drug delivery system, (3) prior to placement of the solid drug
delivery system, a pocket is surgically formed within the sclera to serve
as a receptacle for the solid drug delivery system. For example, in one
administration procedure a surgeon forms a pocket within the sclera of
the eye followed by placement of a solid drug delivery system comprising
the therapeutic agent into the pocket.

[0285] Other administration procedures include, but are not limited to
procedures in which a solid drug delivery system comprising a therapeutic
agent is placed near one or more of the retina choroid or the macula.

[0286] When the therapeutic agent is rapamycin, the solid drug delivery
systems may be used to deliver or maintain an effective amount of
rapamycin in the vitreous. In one nonlimiting example, it is believed
that a delivery system delivering rapamycin in an amount capable of
providing a concentration of rapamycin of 10 pg/ml to 2 .mu.g/ml in the
vitreous may be used for treatment of wet AMD. In another nonlimiting
example, it is believed that a delivery system delivering a concentration
of rapamycin of 0.01 pg/mg to 10 ng/mg in the retina choroid may be used
for treatment of wet AMD. Other effective concentrations are readily
ascertainable by those of skill in the art.

[0287] One method that may be used to deliver the solid drug delivery
systems described herein is delivery by injection. In this method solid
drug delivery systems may be injected or implanted into a subject,
including but not limited to a human subject, or into a position in or
proximal to an eye of the subject for delivery to a subject or to the eye
of a subject. Injection includes but is not limited to intraocular and
periocular placement or injection.

[0288] A "periocular" route of administration means placement near or
around the eye. Nonlimiting examples of placement positions that are in
or proximal to an eye of a subject include intracameral, periocular,
limited to subconjunctival, subtenon, retrobulbar, peribulbar and
posterior juxtascleral delivery.

[0289] Subconjunctival placement may be by injection or other placement of
the solid drug delivery system comprising the therapeutic agent
underneath the conjunctiva, or between the sclera and conjunctiva.
Subtenon placement may be by injection or other placement of the solid
drug delivery system comprising the therapeutic agent into the tenon's
capsule around the upper portion of the eye and into the "belly" of the
superior rectus muscle. Retrobulbar placement may be by injection or
other placement of the solid drug delivery system into the conical
compartment of the four rectus muscles and their intermuscular septa,
behind the globe of the eye. Peribulbar placement may be at a location
external to the confines of the four rectus muscles and their
intramuscular septa, i.e., outside of the muscle cone. Posterior
juxtascleral delivery may be by placement of a therapeutic agent near and
above the macula, in direct contact with the outer surface of the sclera,
and without puncturing the eyeball.

[0290] In some variations the solid drug delivery systems described herein
are placed intraocularly. Intraocular placement includes placement within
the eye.

[0291] Sites to which the solid drug delivery systems may be administered
include but are not limited to the vitreous, aqueous humor, sclera,
conjunctiva, between the sclera and conjunctiva, the retina choroid, the
outer surface of the sclera, the macula, or other area in or proximal to
the eye of a subject. Methods that may be used for placement of the solid
drug delivery systems include but are not limited to injection.

[0292] When the therapeutic agent is rapamycin, the solid drug delivery
systems may be used to deliver or maintain an amount of rapamycin in
tissues of the eye, including without limitation retina, choroid, or the
vitreous, which amount is effective to treat AMD. In one nonlimiting
example, it is believed that a solid drug delivery system delivering
rapamycin in an amount capable of providing a concentration of rapamycin
of 0.1 pg/ml to 2 .mu.g/ml in the vitreous may be used for treatment of
wet AMD. In some nonlimiting examples, it is believed that a solid drug
delivery systems delivering a concentration of rapamycin of 0.1 pg/mg to
1 .mu.g/mg in the retina choroid may be used for treatment of wet AMD.
Other effective concentrations are readily ascertainable by those of
skill in the art based on the teachings described herein.

Intravitreal and Subconjunctival Solid Drug Delivery System Placement for
Delivery of Rapamycin for Treatment of AMD

[0293] In one method described herein, a solid drug delivery system
comprising rapamycin is placed subconjunctivally to prevent, treat,
inhibit, delay onset of, or cause regression of angiogenesis in the eye,
such as to prevent, treat, inhibit, delay onset of, or cause regression
of CNV as observed, for example, in AMD. Rapamycin has been shown to
inhibit CNV in rat and mice models, as described in U.S. application Ser.
No. 10/665,203, which is incorporated herein by reference in its
entirety. Rapamycin has been observed to inhibit Matrigel.TM. and
laser-induced CNV when administered systemically and subretinally. Also,
periocular injection of rapamycin inhibits laser-induced CNV.

[0294] Other therapeutic agents that may be delivered to the eye,
particularly the vitreous of an eye, for treatment, prevention,
inhibition, delaying onset, or causing regression of angiogenesis in the
eye (such as CNV) are members of the limus family of compounds other than
rapamycin including but not limited to everolimus and tacrolimus
(FK-506).

[0295] As described herein, the dosage of the therapeutic agent will
depend on the condition being addressed, whether the condition is to be
treated, prevented, inhibited, have onset delayed, or be caused to
regress, the particular therapeutic agent, and other clinical factors
such as weight and condition of the subject and the route of
administration of the therapeutic agent. It is to be understood that the
methods and solid drug delivery systems described herein have application
for both human and veterinary use, as well as uses in other possible
animals. In some variations the concentration of rapamycin used in the
methods described herein is one that provides 0.1 pg/mg or pg/mg or more
of rapamycin at the tissue level; 1 pg/ml or ng/mg or more at the tissue
level; 0.01 ng/ml or ng/mg or more at the tissue level; 0.1 ng/ml or
ng/mg or more at the tissue level; 0.5 ng/ml or ng/mg or more at the
tissue level; 1 ng/ml or more at the tissue level; 2 ng/ml or more at the
tissue level, 3 ng/ml or more at the tissue level; 5 ng/ml or more at the
tissue level; 10 ng/ml or more at the tissue level; 15 ng/ml or more at
the tissue level; 20 ng/ml or more at the tissue level; 30 ng/ml or more
at the tissue level; or 50 ng/ml or more at the tissue level. One of
ordinary skill in the art would know how to arrive at an appropriate
concentration depending on the route and duration of administration
utilized.

[0296] Generally, the amount of rapamycin administered in a solid drug
delivery system is an amount sufficient to treat, prevent, inhibit,
delaying the onset, or cause regression of the disease or condition of
the eye for the required amount of time.

[0297] In one method, a solid drug delivery system as described herein
containing an amount of rapamycin of between 20 .mu.g and 10 mg is
administered to a human subject for treatment of wet AMD. In another
method, an amount of rapamycin of between 30 .mu.g and 9 mg is
administered to a human subject for treatment of wet AMD. In another
method, an amount of rapamycin of between 10 .mu.g and 90 .mu.g is
administered to a human subject for treatment of wet AMD. In another
method, an amount of rapamycin of between 60 .mu.g and 120 .mu.g is
administered to a human subject for treatment of wet AMD. In another
method, an amount of rapamycin of between 100 .mu.g and 400 .mu.g is
administered to a human subject for treatment of wet AMD. In another
method, an amount of rapamycin of between 400 .mu.g and 1 mg is
administered to a human subject for treatment of wet AMD. In another
method, an amount of rapamycin of between 1 mg and 5 mg is administered
to a human subject for treatment of wet AMD. In another method, an amount
of rapamycin of between 3 mg and 7 mg is administered to a human subject
for treatment of wet AMD. In another method, an amount of rapamycin of
between 5 mg and 10 mg is administered to a human subject for treatment
of wet AMD.

[0298] In another method, a solid drug delivery system as described herein
containing an amount of rapamycin of between 20 .mu.g and 10 mg is
administered to a human subject for treatment of angiogenesis, including
but not limited to choroidal neovascularization. In another method, an
amount of rapamycin of between 30 .mu.g and 9 mg is administered to the
human subject; in another method, an amount of rapamycin of between 10
.mu.g and 90 .mu.g is administered to the human subject; in another
method, an amount of rapamycin of between 60 .mu.g and 120 .mu.g is
administered to the human subject; in another method, an amount of
rapamycin of between 100 .mu.g and 400 .mu.g is administered to the human
subject; in another method, an amount of rapamycin of between 400 .mu.g
and 1 mg is administered to the human subject; in another method, an
amount of rapamycin of between 1 mg and 5 mg is administered to the human
subject; in another method, an amount of rapamycin of between 3 mg and 7
mg is administered to the human subject; in another method, an amount of
rapamycin of between 5 mg and 10 mg is administered to the human subject.

[0299] In one method, a solid drug delivery system as described herein
containing an amount of a therapeutic agent equivalent to an amount of
rapamycin of between 20 .mu.g and 10 mg is administered to a human
subject for treatment of wet AMD. In another method, an amount of a
therapeutic agent equivalent to an amount of rapamycin of between 30
.mu.g and 9 mg is administered to the human subject; in another method,
an amount of a therapeutic agent equivalent to an amount of rapamycin of
between 10 .mu.g and 90 .mu.g is administered to the human subject; in
another method, an amount of a therapeutic agent equivalent to an amount
of rapamycin of between 60 .mu.g and 120 .mu.g is administered to the
human subject; in another method, an amount of a therapeutic agent
equivalent to an amount of rapamycin of between 100 .mu.g and 400 .mu.g
is administered to a human subject for treatment of wet AMD. In another
method, an amount of a therapeutic agent equivalent to an amount of
rapamycin of between 400 .mu.g and 1 mg is administered to the human
subject; in another method, an amount of a therapeutic agent equivalent
to an amount of rapamycin of between 1 mg and 5 mg is administered to the
human subject; in another method, an amount of a therapeutic agent
equivalent to an amount of rapamycin of between 3 mg and 7 mg is
administered to the human subject; in another method, an amount of a
therapeutic agent equivalent to an amount of rapamycin of between 5 mg
and 10 mg is administered to the human subject.

[0300] In another method, a solid drug delivery system as described herein
containing an amount of a therapeutic agent equivalent to an amount of
rapamycin of between 20 .mu.g and 10 mg is administered to a human
subject for treatment of angiogenesis, including but not limited to
choroidal neovascularization. In another method, an amount of a
therapeutic agent equivalent to an amount of rapamycin of between 30
.mu.g and 9 mg is administered to the human subject; in another method,
an amount of a therapeutic agent equivalent to an amount of rapamycin of
between 10 .mu.g and 90 .mu.g is administered to the human subject; in
another method, an amount of a therapeutic agent equivalent to an amount
of rapamycin of between 60 .mu.g and 120 .mu.g is administered to the
human subject; in another method, an amount of a therapeutic agent
equivalent to an amount of rapamycin of between 100 .mu.g and 400 .mu.g
is administered to the human subject; in another method, an amount of a
therapeutic agent equivalent to an amount of rapamycin of between 400
.mu.g and 1 mg is administered to the human subject; in another method,
an amount of a therapeutic agent equivalent to an amount of rapamycin of
between 1 mg and 5 mg is administered to the human subject; in another
method, an amount of a therapeutic agent equivalent to an amount of
rapamycin of between 3 mg and 7 mg is administered to the human subject;
in another method, an amount of a therapeutic agent equivalent to an
amount of rapamycin of between 5 mg and 10 mg is administered to the
human subject.

[0301] Delivery of the therapeutic agents described herein may, for
example, be delivered at a dosage range between 1 ng/day and 100
.mu.g/day, or at dosages higher or lower than this range, depending on
the route and duration of administration. In some variations of solid
drug delivery system used in the methods described herein, the
therapeutic agents are delivered at a dosage range of between 0.1
.mu.g/day and 10 .mu.g/day. In some variations of solid drug delivery
system used in the methods described herein, the therapeutic agents are
delivered at a dosage range of between 1 .mu.g/day and 5 .mu.g/day.
Dosages of various therapeutic agents for treatment, prevention,
inhibition, delay of onset, or cause of regression of various diseases
and conditions described herein can be refined by the use of clinical
trials. Additionally, dose ranges include those disclosed in U.S. Pat.
Nos. 6,376,517 and 5,387,589, the contents of which are hereby
incorporated by reference in their entirety.

[0302] The solid drug delivery systems described herein may be used for
placement in the eye, particularly proximal to the conjunctiva, between
the sclera and conjunctiva, in a surgically introduced scleral flap,
attached or adhered to the sclera, or otherwise proximal to the sclera;
or placement subtenon, posterior juxtascleral, retrobulbar or proximal to
the superior rectus muscle, of therapeutically effective amounts of
rapamycin for extended periods of time to treat, prevent, inhibit, delay
the onset of, or cause regression of CNV, and thus may be used to treat,
prevent, inhibit, delay the onset of, or cause regression of wet AMD. It
is believed that by changing certain characteristics of the solid drug
delivery systems described herein, including but not limited to the
shape, size, positioning and components of the solid drug delivery
systems, the solid drug delivery systems described herein may be used to
deliver therapeutically effective amounts of rapamycin to the eye for a
variety of extended time periods including delivery of therapeutic
amounts for at least 30 days, at least 60 days, at least 90 days, at
least 120 days, at least 150 days, at least 180 days, at least 210 days,
at least 240 days, at least 270 days, at least 300 days, at least 330
days, or at least 360 days.

[0303] For treatment, prevention, inhibition, delaying the onset of, or
causing the regression of certain diseases or conditions, it may be
desirable to maintain delivery of a therapeutically effective amount of
the therapeutic agent for an extended period of time. Depending on the
disease or condition being treated, prevented, inhibited, having onset
delayed, or being caused to regress this extended period of time may be
at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at
least 3 months, at least 6 months, at least 9 months, or at least 1 year.
Generally, however, any extended period of delivery may be possible. A
therapeutically effective amount of agent may be delivered for an
extended period by a solid drug delivery system that maintains for the
extended period a concentration of agent in a subject or an eye of a
subject sufficient to deliver a therapeutically effective amount of agent
for the extended time.

[0304] Delivery of a therapeutically effective amount of the therapeutic
agent for an extended period may be achieved via placement of one solid
drug delivery system or may be achieved by application of two or more
doses of solid drug delivery systems. As a non-limiting example of such
multiple applications, maintenance of the therapeutic amount of rapamycin
for 3 months for treatment, prevention, inhibition, delay of onset, or
cause of regression of wet AMD may be achieved by placement of one solid
drug delivery system delivering a therapeutic amount for 3 months or by
sequential application of a plurality of solid drug delivery systems. The
optimal dosage regime will depend on the therapeutic amount of the
therapeutic agent needing to be delivered, and the period over which it
need be delivered. Those versed in such extended therapeutic agent
delivery dosing will understand how to identify dosing regimes that may
be used based on the teachings provided herein.

[0305] Delivery of the therapeutic agents described herein may, for
example, be delivered at a dosage range between 1 ng/day and 100
.mu.g/day, or at dosages higher or lower than this range, depending on
the route and duration of administration. In some variations of solid
drug delivery systems used in the methods described herein, the
therapeutic agents are delivered at a dosage range of between 0.1
.mu.g/day and 10 .mu.g/day. In some variations of solid drug delivery
systems used in the methods described herein, the therapeutic agents are
delivered at a dosage range of between 1 .mu.g/day and 5 .mu.g/day.
Dosages of various therapeutic agents for treatment, prevention,
inhibition, delay of onset, or cause of regression of various diseases
and conditions described herein can be refined by the use of clinical
trials.

[0306] When a therapeutically effective amount of rapamycin is
administered to a subject suffering from wet AMD, the rapamycin may
treat, inhibit, or cause regression of the wet AMD. Different
therapeutically effective amounts may be required for treatment,
inhibition or causing regression. A subject suffering from wet AMD may
have CNV lesions, and it is believed that administration of a
therapeutically effective amount of rapamycin may have a variety of
effects, including but not limited to causing regression of the CNV
lesions, stabilizing the CNV lesion, and preventing progression of an
active CNV lesion.

[0307] When a therapeutically effective amount of rapamycin is
administered to a subject suffering from dry AMD, it is believed that the
rapamycin may prevent or slow the progression of dry AMD to wet AMD.

Methods of Administering an Anti-Proliferative Agent Proximal to an
Ocular Device

[0308] In some variations, an ocular condition is treated by administering
an anti-proliferative agent proximal to an ocular device.

[0309] In some variations the ocular device is a glaucoma drainage device.

[0310] Most generally, a glaucoma drainage device is any device capable of
being used for draining fluid from the aqueous humor of an eye. Glaucoma
Drainage Devices include but are not limited to devices that include
shunts, stents, tubes, membranes and valves and combinations of these
components. Glaucoma Drainage Devices include but are not limited to
those described in U.S. Pat. Nos. 6,007,510 and 6,142,969, the contents
of which are incorporated herein by reference in their entirety; the
Optonol Ex-Press.TM. Miniature Glaucoma Implant (510(k) number K012852);
the Ahmed Glaucoma Valve (510(k) number K980657); the OptiMed Glaucoma
Shunt (510(k) number K903462); and the Baerveldt Glaucoma Shunt (510(k)
numbers K905129 and K955455). Additional glaucoma drainage devices
include but are not limited to those described in U.S. 60/666,872, filed
Mar. 30, 2005 with attorney docket number 57796-30007.00, titled GLAUCOMA
DRAINAGE DEVICES.

[0311] Once implanted in a subject, ocular devices such as glaucoma
drainage devices may cause cellular proliferation that may result in the
device ceasing to function, or having a reduced useful lifetime.
Described herein are devices and methods for use of ocular devices with
one or more anti-proliferative agents. The anti-proliferative agent may
be coated onto the glaucoma drainage device, may be incorporated into
materials used to make the glaucoma drainage device, or a source of
anti-proliferative agent may be administered to provide the
anti-proliferative agent proximal to an implanted glaucoma drainage
device, as described further in U.S. 60/666,872, filed Mar. 30, 2005 with
attorney docket number 57796-30007.00, titled GLAUCOMA DRAINAGE DEVICES.
In the methods, devices, and compositions described herein, unless the
context makes clear otherwise, one or more than one anti-proliferative
agent may be used. Anti-proliferative agents that may be used are
described herein, including but not limited to in the section titled
Anti-Proliferative Agents for Use With Ocular Devices herein or in U.S.
60/666,872, filed Mar. 30, 2005 with attorney docket number
57796-30007.00, titled GLAUCOMA DRAINAGE DEVICES.

[0312] In some variations of the methods, devices, and compositions
described herein the anti-proliferative agent is rapamycin.

[0313] Described herein are methods of using Glaucoma Drainage Devices in
which the Glaucoma Drainage Device is used in combination with a source
of one or more anti-proliferative agents. Generally any source may be
used that is capable of delivering the anti-proliferative agent or agents
in an amount, for a time period, and to a position capable of reducing
cell proliferation caused by implantation of the Glaucoma Drainage
Device. In addition to the solid drug delivery systems described herein,
sources of anti-proliferative agent or agents that may be used include
but are not limited to solid implants containing anti-proliferative agent
or agents, self-emulsifying formulations, liquid formulations, solutions,
suspensions, formulations capable of forming a gel containing the
anti-proliferative agent or agents when the formulation is placed in a
medium of the eye, in situ gelling formulations, emulsions, and
formulations capable of forming a non-dispersed mass containing the
anti-proliferative agent or agents when the formulation is placed in a
medium of the eye. Sources of anti-proliferative agent or agents that may
be used include but are not limited to the formulations and devices
described in the following patent applications, each of which is
incorporated herein by reference in its entirety: application Ser. No.
10/665,203, filed Sep. 18, 2003, with attorney docket number
559092000100, titled METHOD OF INHIBITING CHOROIDAL NEOVASCULARIZATION;
application Ser. No. 10/945,682 filed Sep. 20, 2004, with attorney docket
number 577962000100, titled TRANSSCLERAL DELIVERY; application No.
60/651,790, filed Feb. 9, 2005, with attorney docket number 577963000200,
titled FORMULATIONS FOR OCULAR TREATMENT; application 60/664,040, filed
Mar. 21, 2005, with attorney docket number 577963000400, titled LIQUID
FORMULATIONS FOR TREATMENT OF DISEASES OR CONDITIONS; application
60/664,119, filed Mar. 21, 2005, with attorney docket number
577963000500, titled DRUG DELIVERY SYSTEMS FOR TREATMENT OF DISEASES OR
CONDITIONS; application 60/664,306, filed Mar. 21, 2005, with attorney
docket number 577963000600, titled 1N SITU GELLING FORMULATIONS AND
LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR CONDITIONS; application
Ser. No. 11/351,844 filed Feb. 9, 2006, with attorney docket number
57796-2000200, titled FORMULATIONS FOR OCULAR TREATMENT; application Ser.
No. 11/351,761 filed Feb. 9, 2006, with attorney docket number
57796-2000400, titled LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR
CONDITIONS; and application 60/772,018 filed Feb. 9, 2006, with attorney
docket number 57796-3001000, titled STABLE FORMULATIONS.

[0314] The source of anti-proliferative agent may be separate from or
attached to the Glaucoma Drainage Device. As a nonlimiting example, the
source of anti-proliferative agent may be any solid drug delivery device
or other formulation capable of releasing the anti-proliferative agent
and the solid structure may be attached to or incorporated into the
Glaucoma Drainage Device. Solid structures capable of releasing the
anti-proliferative agent that may be used include but are not limited to
an anti-proliferative agent containing reservoir.

[0315] In some variations, the solid drug delivery systems described
herein are used to treat glaucoma. In some variations, the solid drug
delivery systems described herein for treating glaucoma comprise a limus
compound such as rapamycin, and are used as a surgical adjuvant to
prevent, reduce or delay surgical complications. In some variations, the
solid drug delivery systems described herein for treating glaucoma
comprise a limus compound such as rapamycin, and are used to improve or
prolong surgical implant success. In some variations, the solid drug
delivery systems described herein for treating glaucoma comprise a limus
compound such as rapamycin, and are used to improve or prolong success of
an argon laser trabeculectomy or other glaucoma-related surgery. In some
variations, the solid drug delivery systems described herein have a
neuroprotective effect and are used to treat glaucoma.

[0316] The source of anti-proliferative agent may be placed in the
appropriate position in the eye using any method capable of placing the
source including but not limited to by injection and by placement of a
solid drug delivery device. In one device-source combination described
herein, the source of anti-proliferative agent may be placed outside of
the sclera and may deliver the anti-proliferative agent transsclerally.

[0317] In one combination device and anti-proliferative agent source
described herein, the device has the form of a device as shown in FIG. 1
of U.S. Pat. No. 6,142,969, or other similar version of the device as
shown in other Figures in this patent. In one such device source
combination, the source of anti-proliferative agent is a solid device
that may be placed proximal to the tube end labeled 16. In another such
device-source combination, the source of anti-proliferative agent is a
solid device that may be placed proximal to the portion labeled 24 in
FIG. 1. In another such device source combination, the source of
anti-proliferative agent is a structure that is permeable or
semi-permeable to the fluids of the aqueous humor and that is placed
inside the tube labeled 12 in FIG. 1. In one such device, the permeable
or semi-permeable structure is placed proximal to the tube end labeled 16
in FIG. 1. In one such device, the permeable or semi-permeable structure
is a mesh-like structure or sponge like structure, or a porous foam
structure that incorporates the anti-proliferative agent and thus can act
as a source of the anti-proliferative agent.

[0318] Also described herein are kits containing any of the Glaucoma
Drainage Devices described herein and any one or more of the
anti-proliferative agent sources described herein.

[0319] Also described herein are methods of draining fluid from the
aqueous humor by use of a Glaucoma Drainage Device described herein
together with use of any one or more of the anti-proliferative agent
sources described herein. Generally the combinations of the Glaucoma
Drainage Devices and sources of anti-proliferative agent sources
described herein can be used for addressing any of the diseases or
conditions that may be addressed using the Glaucoma Drainage Devices
alone, including but not limited to those diseases and conditions
described in the articles in U.S. 60/666,872 and U.S. Pat. Nos. 6,007,510
and 6,142,969.

[0320] In some variations, the formulations or solid drug delivery devices
comprising an anti-proliferative agent deliver an amount of the
therapeutica gent effective to reduce cellular proliferation proximal to
the ocular device for a period of at least 14, at least 30, at least 45,
at least 60, at least 90, or at least 105 days following placement of the
solid drug delivery system proximal to the ocular device.

Anti-Proliferative Agents for Use with Ocular Devices

[0321] In some variations, the methods and formulations described herein
comprise an anti-proliferative agent. In some variations the
anti-proliferative agent is any anti-proliferative agent which has the
desired effect. In some variations the anti-proliferative agent is any
anti-proliferative agent described in the Therapeutic Agents section. In
some variations the anti-proliferative agent is a limus compound or an
immunophilin binding compound as described in the Therapeutic Agents
section. In some variations the anti-proliferative agent is a steroidal
agent as described in the Therapeutic Agents section, and in some
variations the steroidal agent is present in the amounts described in the
Therapeutic Agents section. In some variations the anti-proliferative
agent is a combination of therapeutic agents. In some variations the
anti-proliferative agent is used in combination with one or more other
therapies or therapeutic agents, including but not limited to those
therapeutic agents listed for combination therapy in the Therapeutic
Agents section.

[0322] In some variations the antiproliferative agent is one or more of
those disclosed in the following patents and publications, the contents
of each of which is incorporated herein by reference in its entirety: PCT
publication WO 2004/027027, published Apr. 1, 2004, titled Method of
inhibiting choroidal neovascularization, assigned to Trustees of the
University of Pennsylvania; U.S. Pat. No. 5,387,589, issued Feb. 7, 1995,
titled Method of Treating Ocular Inflammation, with inventor Prassad
Kulkarni, assigned to University of Louisville Research Foundation; U.S.
Pat. No. 6,376,517, issued Apr. 23, 2003, titled Pipecolic acid
derivatives for vision and memory disorders, assigned to GPI NIL
Holdings, Inc; PCT publication WO 2004/028477, published Apr. 8, 2004,
titled Method subretinal administration of therapeutics including
steroids: method for localizing pharmadynamic action at the choroid and
retina; and related methods for treatment and or prevention of retinal
diseases, assigned to Innorx, Inc; U.S. Pat. No. 6,416,777, issued Jul.
9, 2002, titled Ophthalmic drug delivery device, assigned to Alcon
Universal Ltd; U.S. Pat. No. 6,713,081, issued Mar. 30, 2004, titled
Ocular therapeutic agent delivery device and methods for making and using
such devices, assigned to Department of Health and Human Services; U.S.
Pat. No. 5,100,899, issued Mar. 31, 1992, titled Methods of inhibiting
transplant rejection in mammals using rapamycin and derivatives and
prodrugs thereof.

[0324] A solid drug delivery system comprising rapamycin was prepared with
the following components, where the percent is the weight of the
component per weight of the total: 47.7% rapamycin (obtained from LC
laboratories (Woburn, Mass.), and Chunghwa Chemical Synthesis & BioTech.
Co, Ltd (Taiwan)), 23.25% PVP K90 (obtained from BASF), 23.25% Eudragit
RL100 (obtained from Rohm Pharma Polymers), and 5.8% PEG 400 (obtained
from DOW Chemical). Briefly, Eudragit RL 100 was added to a mixture of
pure ethanol and PEG 400 in a bottle. Eudragit RL 100 was dissolved by
vigorous shaking using a vortex mixer. PVP 90 was added to the solution
of PEG 400, Ethanol and Eudragit RL 100. PVP 90 was also dissolved using
vortex mixer. Rapamycin was added finally and mixed well to get a uniform
solution. This solution was viscous and sticky. The solution was cast as
a film on a silicone-coated polyester film, using a roll-over Gardner
Knife at desired thickness. The wet film was dried under the hood
overnight to drive off (evaporate) ethanol. Once the ethanol was driven
off, the film was dried and peeled off. The film was die-cut into wafers
at desired diameter circles.

Example 2

Subconjunctival Placement of a Rapamycin-Containing Solid Drug Delivery
System

[0325] Approximately 1.5-2.5 mg of the solid drug delivery system
described in Example 1 were placed into the area between the sclera and
the conjunctiva of the eye of New Zealand white rabbits. Briefly, the
solid drug delivery system was inserted into the subconjunctival space by
a small cut of the conjunctiva with a vannas scissor, and inserted using
tying forceps. After the solid drug delivery system was placed under the
conjunctiva, the conjunctiva was closed with one or two sutures.

[0326] FIG. 1 depicts the level of rapamycin present in the vitreous
(ng/ml), retina choroid (ng/mg), and sclera (ng/mg) at 1, 14, 28, 75, 95,
and 107 days after placement of the solid drug delivery system.

[0327] The analysis was performed by LCMS (liquid chromatography mass
spectroscopy) after dissection of the eye into the tissues specified
below. Day 1, 14 and 28 timepoints represents the average of two eyes of
each of two rabbits (four eyes at each timepoint); the day 75 timepoint
represents the average of two eyes of one rabbit; the day 95 timepoint
represents the average of two eyes of one rabbit and one eye of another
rabbit; the day 107 timepoint represents the average of two eyes of one
rabbit.

[0328] The full vitreous was homogenized and analyzed. The average
concentration of the vitreous was calculated by dividing the mass of
rapamycin measured by the volume of vitreous analyzed. The sample did not
include the solid drug delivery system; thus, this measurement indicated
the level of rapamycin delivered to the vitreous via the solid drug
delivery system.

[0329] The average level of rapamycin in the vitreous at 1, 14, 28, 75, 95
and 107 days after subconjunctival placement was about 11.35, about
5.025, about 8.325, about 13, 0.83, and about 6.43 ng/ml, respectively.

[0330] The full retina choroid was homogenized and analyzed. The average
concentration of the retina choroid was calculated by dividing the mass
of rapamycin measured by the mass of retina choroid analyzed. The sample
did not include the solid drug delivery system; thus, this measurement
indicated the level of rapamycin delivered to the retina choroid via the
solid drug delivery system.

[0331] The average level of rapamycin in the retina choroid at 1, 14, 28,
75, 95, and 107 days after subconjunctival placement of the solid drug
delivery system was about 1.0716, 0.11975, about 0.27775, about 0.161,
about 0.07, and about 0.037 ng/mg, respectively.

[0332] The sclera was analyzed in the same way as the retina choroid. The
scleral sample may have included the solid drug delivery system; thus,
this measurement likely indicated clearance of rapamycin from the sclera,
but some inaccuracy may have been introduced due to sampling.

[0333] The average level of rapamycin in the sclera at 1, 14, 28, 75, 95
and 107 days after subconjunctival placement of the solid drug delivery
system was about 1.517, 0.51, 1.40675, 0.1265, 0.06, and 0.27 ng/mg,
respectively.

Example 3

Rapamycin-Containing Solid Drug Delivery System

[0334] A solid drug delivery system comprising rapamycin was prepared with
the following components, where the percent is per weight of the total:
10.2% rapamycin, 89.8% PVP K90. Rapamycin and PVP K-90 were dissolved in
ethanol, a film was cast on a release coated paper, dried to evaporate
the solvent, and the resultant wafer was die-cut into its size and shape.

Example 4

Subconjunctival Placement of a Rapamycin-Containing Solid Drug Delivery
System

[0335] Approximately 1 mg of the solid drug delivery system described in
Example 3 were placed into the area between the sclera and the
conjunctiva of the eye of New Zealand white rabbits as described in
Example 2.

[0336] FIG. 2 depicts the level of rapamycin present in the vitreous
(ng/ml) at 1, 5, 7 and 8 days after placement of the solid drug delivery
system.

[0337] The analysis was by liquid chromatography and mass spectroscopy.
All timepoints represents the average of two eyes of one rabbit.

[0338] The full vitreous was homogenized and analyzed. The average
concentration of the vitreous was calculated by dividing the mass of
rapamycin measured by the volume of vitreous analyzed. The sample did not
include the solid drug delivery system; thus, this measurement indicated
the level of rapamycin delivered to the vitreous via the solid drug
delivery system.

[0339] The average level of rapamycin in the vitreous at 1, 5, 7 and 8
days after subconjunctival placement of the solid drug delivery system
was about 68.70, 5.50, 0.80, and 0.85 ng/ml, respectively.

[0340] FIG. 3 depicts the level of rapamycin present in the retina choroid
(ng/mg) at 1, 5, 7, and 8 days after placement of the solid drug delivery
system.

[0341] The full retina choroid was homogenized and analyzed. The average
concentration of the retina choroid was calculated by dividing the mass
of rapamycin measured by the mass of retina choroid analyzed. The sample
did not include the solid drug delivery system; thus, this measurement
indicated the level of rapamycin delivered to the retina choroid via the
solid drug delivery system.

[0342] The average level of rapamycin in the retina choroid at 1, 5, 7,
and 8 days after subconjunctival placement of the solid drug delivery
system was about 0.285, 0.025, 0.0435, and 0.0165 ng/mg, respectively.

Example 5

Rapamycin-Containing Solid Drug Delivery System

[0343] A solid drug delivery system comprising rapamycin was prepared with
the following components, where the percent is the weight of the
component per weight of the total: 45.13% rapamycin (obtained from LC
laboratories (Woburn, Mass.), and Chunghwa Chemical Synthesis & BioTech.
Co, Ltd (Taiwan)), 40.03% PVP K90 (obtained from BASF), 9.7% Eudragit
RL100 (obtained from Rohm Pharma Polymers), and 5.14% PEG 400 (obtained
from DOW Chemical). This solid drug delivery system was prepared as in
Example 1.

Example 6

Subconjunctival Placement of a Rapamycin-Containing Solid Drug Delivery
System

[0344] Approximately 1.5-2.5 mg of the solid drug delivery system
described in Example 5 were placed between the sclera and the conjunctiva
of the eye of New Zealand white rabbits as described in Example 2.

[0345] FIG. 4 depicts the level of rapamycin present in the vitreous
(ng/ml), retina choroid (ng/mg), and sclera (ng/mg) at 14, 42, 63, and 91
days after placement of the solid drug delivery system.

[0346] The analysis was performed by LCMS (liquid chromatography-mass
spectroscopy). Day 14, 42, 63, and 91 timepoints each represent the
average of two eyes of each of two rabbits (four eyes at each timepoint).

[0347] The full vitreous was homogenized and analyzed. The average
concentration of the vitreous was calculated by dividing the mass of
rapamycin measured by the volume of vitreous analyzed. The sample did not
include the solid drug delivery system; thus, this measurement indicated
the level of rapamycin delivered to the vitreous via the solid drug
delivery system.

[0348] The average level of rapamycin in the vitreous at 14, 42, 63, and
91 days after subconjunctival placement of the solid drug delivery
systemation was about 5.7, about 2.6, about 5.7, and about 9.3 ng/ml,
respectively.

[0349] The full retina choroid was homogenized and analyzed. The average
concentration of the retina choroid was calculated by dividing the mass
of rapamycin measured by the mass of retina choroid analyzed. The sample
did not include the solid drug delivery system; thus, this measurement
indicated the level of rapamycin delivered to the retina choroid via the
solid drug delivery system.

[0350] The average level of rapamycin in the retina choroid at 14, 42, 63,
and 91 days after subconjunctival placement of the solid drug delivery
system was about 3.3, 6.3, about 0.41, and about 0.27 ng/mg,
respectively.

[0351] The sclera was analyzed in the same way as the retina choroid. The
scleral sample may have included the solid drug delivery system; thus,
this measurement likely indicated clearance of rapamycin from the sclera,
but some inaccuracy may have been introduced due to sampling.

[0352] The average level of rapamycin in the sclera at 14, 42, 63, and 91
days after subconjunctival placement of the solid drug delivery system
was about 164, 14.6, 1.75, and 2.1 ng/mg, respectively.

Example 7

Rapamycin-Containing Solid Drug Delivery Systems

[0353] A solid drug delivery system comprising rapamycin was prepared with
the following components, where the percent is the weight of the
component per the weight of the total: 19.33% rapamycin, 21.78% PVP K90,
24.56% PEG 400, and 34.33% pure ethanol. Briefly, PVP and Rapa were added
to a mixture of of PEG 400 and pure ethanol in a bottle, and the mixture
was vigorously mixed to obtain a uniform viscous suspension. The viscous
suspension was applied onto a backing in the shape of a microcup using a
spatula.

[0354] The microcup was made of a non-bioerodible thermoplastic
polyetheretherketone. The microcups were made by injection molding using
a Battenfeld Microsystem 50 system, and were shaped as a thin, shallow
saucer. The microcups were prepared by Rapiwerks, LLC.

Example 8

Subconjunctival Placement of a Rapamycin-Containing Solid Drug Delivery
System

[0355] Approximately 0.5 mg of the solid drug delivery system described in
Example 7 were placed between the sclera and the conjunctiva of the eye
of New Zealand white rabbits as described in Example 2. The therapeutic
agent portion of the solid drug delivery system was placed against the
sclera, where it adheres due to ocular moisture. The microcup portion of
the solid drug delivery system was oriented towards the conjunctiva, to
limit diffusion of rapamycin towards the conjunctiva.

[0356] FIG. 5 depicts the level of rapamycin present in the aqueous humor
(ng/ml) at 21, 35, and 37 days after placement of the solid drug delivery
system.

[0357] About 50 .mu.l to about 100 .mu.l were removed from the eye of a
rabbit by tuberculin syringe with a 29-30 gauage needle while the rabbit
was living. The amount of aqueous humor removed determined, and the
sample was frozen and later analyzed. The analysis was by liquid
chromatography mass spectroscopy. All timepoints represent the average of
two eyes of one rabbit.

[0358] The average concentration of the aqueous humor was calculated by
dividing the mass of rapamycin measured by the volume of aqueous humor
analyzed. The sample did not include the solid drug delivery system;
thus, this measurement indicated the level of rapamycin delivered to the
aqueous humor via the solid drug delivery system.

[0359] The day 21 sample was an average of each of two eyes of each of two
rabbits (four eyes total); the day 35 sample was a single rabbit eye; the
day 37 sample was an average of each of two eyes. The average level of
rapamycin in the aqueous humor at 21, 35, and 37 days after
subconjunctival placement of the solid drug delivery system was about
0.76, 0.056, and 0.09 ng/ml, respectively.

Example 9

[0360] A solid drug delivery system comprising rapamycin was prepared with
the following components, where the percent is the weight of the
component per weight of the total: 44.62% rapamycin (obtained from LC
laboratories (Woburn, Mass.), and Chunghwa Chemical Synthesis & BioTech.
Co, Ltd (Taiwan)), 39.77% PVP K90 (obtained from BASF), 9.93% Eudragit
RL1000 (obtained from Rohm Pharma Polymers), and 5.68% PEG 400 (obtained
from DOW Chemical). This solid drug delivery system was prepared as in
Example 1.

[0361] The solid drug delivery system was stored at 5.degree. C., and had
the stability shown in Table 2, below.